Roles and therapeutic prospects of the laminin family in disorders of the nervous system

Abstract

Background

Neurological disorders comprise a heterogeneous spectrum—including cerebrovascular disease, neurodegeneration, autoimmune demyelination, neuropsychiatric conditions, and trauma—whose incidence and prevalence are rising with population aging, creating sustained healthcare and socioeconomic burdens. Recent work highlights laminin, a major non-collagenous BM glycoprotein, as a key regulator of central nervous system structure and function. As a core extracellular matrix scaffold and signaling hub, laminin orchestrates matrix remodeling, barrier disruption/repair, neuroinflammation, and neuronal plasticity; it contributes to neurodevelopment and axon guidance, synaptogenesis and plasticity, myelination and nodal microarchitecture, and the homeostasis of the blood–brain barrier and neurovascular unit.

Methods

Based on a comprehensive literature review, this article systematically elaborates the structure and classification of laminin, its spatiotemporal distribution and physiological roles in the central nervous system, as well as the molecular mechanisms and network effects in neurological diseases. Furthermore, it evaluates the feasibility and challenges of laminin-targeted therapies, aiming to provide insights for the development of innovative precision interventions.

Conclusion

This review systematically demonstrates that the laminin family functions not merely as a “structural hub of the basement membrane,” but also holds substantial promise as an “actionable target” for neurological disorders. Through a parallel receptor network comprising integrins, α-dystroglycan, and heparan sulfate proteoglycans/syndecans, laminin couples mechanical support with signal transduction, occupying a central position in the development, homeostatic maintenance, and repair of the blood–brain barrier/neurovascular unit, synaptic architecture, and the myelin–Nodes of Ranvier microstructure. Future investigations should elucidate the profound mechanistic roles of laminin family members in neurological diseases and advance targeted therapeutic development, thereby facilitating novel strategies for the prevention and treatment of neurological disorders.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-026-08410-9.

Introduction

Neurological disorders are a broad class of conditions that affect the structure or function of the central, peripheral, and autonomic nervous systems, encompassing cerebrovascular diseases (ischemic stroke (IS)/hemorrhagic stroke (HS)), neurodegenerative diseases (e.g., Alzheimer’s disease (AD) and Parkinson’s disease (PD)), epilepsy, demyelinating diseases (e.g., multiple sclerosis (MS)), neuroinfectious and inflammatory conditions, neurotrauma (traumatic brain injury (TBI)/spinal cord injury), and peripheral nerve and neuromuscular diseases. The latest Global Burden of Disease (GBD 2021) analysis indicates that in 2021 approximately 3.4 billion people worldwide had experienced a neurological disorder, making it the leading cause of health loss globally [1]; compared with 1990, population aging and cumulative risk exposures have driven a sustained rise in the absolute burden of disability and mortality attributable to neurological diseases [2]. In 2024, the World Health Organization similarly reported that “at least one in three people” is affected by neurological conditions, underscoring immense pressures on prevention, healthcare, and long-term care systems [3].

Regarding the state of research and public health impact, neurological disorders are generally characterized by protracted courses, high recurrence rates, substantial disability, and substantial caregiving costs, while truly disease-modifying interventions remain limited [4]. Pathophysiological inquiry has shifted from a neuron-centric view to the neurovascular unit (NVU) framework, emphasizing that dysregulated coupling among endothelial cells, pericytes, astrocytes, microglia, and neurons is central to ischemia–reperfusion injury, chronic inflammation, and metabolic derangement [5]. This framework helps explain a spectrum of phenotypes from microcirculatory hypoperfusion to network-level declines in functional connectivity. Meanwhile, the structure and transport properties of the blood–brain barrier (BBB) prevent > 90% of conventional small- and large-molecule therapeutics from entering the central nervous system (CNS), severely constraining pharmacodynamic validation and clinical translation. Although recent strategies—leveraging endogenous transporters, receptor-mediated transcytosis, nano-/liposomal carriers, mechanical opening (e.g., focused ultrasound), and intranasal–brain delivery—have advanced rapidly, trade-offs among permeability gain, temporal control, and safety margins remain a key bottleneck [6]. Against this backdrop, three cross-cutting priorities emerge: (i) reproducible, progression-oriented biomarker systems integrating imaging, biofluids, and electrophysiology [7–10]; (ii) BBB-transcending, in vivo controllable delivery platforms tailored to disease entities and therapeutic windows [11–15]; and (iii) novel targets capable of concurrently restoring microcirculatory, inflammatory, and metabolic homeostasis [16–19]. Within the NVU, the extracellular matrix (ECM) and vascular basement membrane (BM) have become focal points: composed of type IV collagen, heparan sulfate proteoglycans (HSPGs), nidogen, and laminins, this 3D network forms the structural core of the BBB and critically governs endothelial polarity, adhesion, tight-junction integrity, and inflammatory flux [20]. Under pathological conditions, matrix metalloproteinases (MMP-2/9) and others degrade BM proteins and precipitate BBB leakage, suggesting that ECM/BM–oriented repair could have broad applicability and translational value [21, 22].

Among ECM constituents, the laminin family has drawn intense interest for its dual “structure-and-signal” roles at the vascular BM and the astrocytic endfoot–endothelial interface. Laminins are among the most important non-collagenous BM glycoproteins, forming heterotrimeric αβγ assemblies with cruciform/fan-shaped multidomain architectures that provide mechanical support and mediate adhesion and signaling [23]. The human genome encodes LAMA1–5, LAMB1–3, and LAMC1–3; combinatorial pairing yields more than a dozen isoforms (e.g., laminin-211, -411, -511/-521). Contemporary nomenclature denotes isoforms by chain identities (e.g., “511” indicates α5β1γ1). These isoforms display striking spatiotemporal specificity across tissues, cell types, and developmental stages, and they cooperate with receptors (integrins α6β1/α3β1/α6β4, dystroglycan, etc.) to determine cell fate and barrier homeostasis [24, 25]. Over the past two decades, consensus has emerged that laminins serve as both scaffold and signaling organizers of BM assembly and homeostasis: via N-terminal polymerization domains and interactions with nidogen, type IV collagen, and HSPGs, they build a 3D network that influences cell polarity, migration, differentiation, and stem-cell maintenance; genetic and in vivo studies indicate that isoforms are partially complementary yet not fully interchangeable [26, 27]. In the CNS, laminins secreted by endothelial cells, pericytes, and astrocytic endfeet form the abluminal and luminal layers of the vascular BM and are essential for BBB integrity; multiple reviews and in vivo studies show that selective deletion of specific chains/receptors induces BBB breakdown, leakage, and amplified neuroinflammation [28, 29].

As candidate biomarkers, laminins and laminin-related BM fragments have been studied in both preclinical models and human observational cohorts of brain injury and neuroinflammation. In animal and experimental systems, tissue, CSF, and blood changes in BM constituents often parallel BBB disruption and NVU remodeling; in humans, however, the current evidence is largely observational and remains insufficient for defining laminin markers as disease-specific or clinically validated indicators. At present, these signals are more appropriately viewed as context-dependent candidate markers of barrier injury/repair rather than definitive standalone biomarkers [30]. Therapeutically, laminin-derived functional fragments and mimetic peptides (e.g., IKVAV) as well as E8 domains have been integrated into biomaterials and regenerative platforms to promote stem-cell adhesion, growth, and neural differentiation, enhancing neurite outgrowth and functional readouts in animal and in vitro models—thereby offering feasible routes for ECM-targeted repair. Functionalized hydrogels and nanoplatforms that combine these motifs with controlled release and local delivery are viewed as potential solutions to BBB constraints [31–33]. In IS, TBI, MS, and other neurological diseases, BBB disruption and neuroinflammation–metabolic imbalance are shared pathologies, and vascular-BM laminin isoforms—particularly -411 and -511/-521—directly regulate endothelial adhesion, tight junctions, and transendothelial transport. Under pathological conditions, selective proteolysis by MMP-2/9 rapidly weakens the barrier, fostering leukocyte/molecular extravasation and perturbing axonal and synaptic microenvironments. Consequently, precision interventions targeting specific isoform–receptor axes are expected to yield dual benefits—“barrier repair + modulation of inflammation/plasticity”—and can be paired with imaging/fluid biomarkers for stratification and response monitoring. Recent reviews (2023–2025) consistently identify “laminin-focused BBB regulation” as a promising avenue for discovering new targets and material–drug combination strategies [28, 29, 34].

In light of the growing depth of laminin biology and its close ties to the pathogenesis of CNS diseases, this review aims to synthesize the roles and significance of laminins across major neurological conditions. We first detail our literature-search strategy and inclusion criteria (databases and keywords) to comprehensively cover neuroscience and laminin-related studies. We then recount the historical trajectory of laminin research and, from structural biology and molecular diversity, clarify the isoform repertoire arising from distinct α/β/γ-chain combinations and their receptor interactomes. Building on this foundation, we summarize the spatiotemporal distribution and physiological roles of laminins in the healthy CNS—highlighting neurodevelopment and axon guidance, synaptogenesis and plasticity, myelination and the microarchitecture of the nodes of Ranvier, and the maintenance of BBB and NVU homeostasis. We next examine laminin dysregulation across major neurological contexts. For disorders such as stroke, BBB dysfunction, MS, and neurodevelopment-related processes, mechanistic and translational evidence is comparatively better developed. By contrast, in AD, PD, ALS, depression, and anxiety, current evidence remains more heterogeneous and, in several cases, still emerging; accordingly, these areas are discussed more cautiously to avoid overstating mechanistic certainty or translational readiness. Finally, we outline current limitations—including biological complexity, model and methodological constraints, delivery/formulation challenges, safety and specificity concerns, and translational and standardization gaps—and propose future directions that could accelerate the clinical translation of laminin-targeted strategies. By systematically presenting the structure–function relationships of laminins and their broad impact on brain pathophysiology, we aim to provide an authoritative resource for researchers, clinicians, and drug developers; a deeper understanding of laminin signaling networks in the CNS may catalyze innovative prevention and treatment strategies, optimize disease management, and open opportunities to mitigate—or even reverse—disabling neurological disorders.

Methods

We conducted a systematic literature search using two sets of keywords. The first comprised disease-related terms (Keyword Set 1): “neurological disorders,” “stroke,” “ischemic stroke,” “hemorrhagic stroke,” “vascular cognitive impairment,” “Alzheimer’s disease,” “Parkinson’s disease,” “multiple sclerosis,” “amyotrophic lateral sclerosis,” “depression,” “anxiety,” and “traumatic brain injury.” The second comprised molecule-related terms (Keyword Set 2): “laminin,” “LAMA,” “LAMB,” and “LAMC.” To broaden coverage, we additionally included synonyms and Medical Subject Headings (MeSH). Searches were performed across Google Scholar, PubMed, ScienceDirect, MEDLINE, Embase, and Web of Science, spanning the 1970s through the 2020s. All retrieved records were systematically reviewed to identify articles relevant to the study topic, with duplicates and non-relevant studies excluded. To ensure rigor and reproducibility, the search and screening procedures were conducted independently by the investigators and cross-verified.

A historical timeline of laminin research

The trajectory of Laminin research spans more than four decades and represents a major thread linking ECM biology with neuroscience. In 1979, Timpl and colleagues first isolated Laminin, a large non-collagenous glycoprotein from the BM of Engelbreth–Holm–Swarm (EHS) mouse tumors, revealing a key BM component beyond collagen [35]. By 1983, Laminin was shown to strongly promote neurite outgrowth, identifying it as an essential cue for neurodevelopment and axon guidance [36]. Between 1988 and 1990, Sonnenberg and others identified α6β1 integrin as a principal Laminin receptor, establishing the Laminin–integrin adhesion and signaling axis [37]. In 1994, Burgeson and colleagues proposed a unified α/β/γ chain nomenclature for Laminins [38], and in 1995 mutations in human LAMA2 were linked to merosin-deficient congenital muscular dystrophy (MDC1A), connecting Laminin deficiency to human neuromuscular disease [39]. Structural advances followed: in 1999 the crystal structure of the Laminin G (LG) domain clarified the basis of dystroglycan recognition [40], and by 2004 Laminin was described as a central organizer of BM assembly [41]. In 2005, Aumailley et al. introduced the widely adopted three-digit isoform nomenclature (e.g., Laminin-511, -521, -211), facilitating systematic ECM research [42]. Subsequent studies further revealed that LARGE-mediated glycosylation governs Laminin–dystroglycan binding, explaining receptor inactivation in muscular dystrophy [43]. In 2017, expression of linker proteins such as αLNNd and mini-agrin restored BM polymerization and neural function in LAMA2-deficient models, exemplifying ECM-targeted therapy [44]. In 2021, the structure of α6β1 integrin bound to Laminin-511 was resolved, enabling rational design of receptor modulators [45]. Recent studies (2023–2025) highlight Laminin—particularly α5-containing isoforms—as a key regulator of BBB integrity, immune cell transmigration, and neuroinflammation, positioning it as a therapeutic target for neurological disease and ECM-engineered neural repair [28, 29, 46] (Table 1).

Table 1.

Laminin research milestones

Period	Milestone	Key Point	Theme	Reference
1979	Discovery	Timpl et al. isolate a large non-collagenous BM glycoprotein from EHS tumors and name it Laminin.	Discovery	[35]
1983	Neurite outgrowth	Laminin potently promotes neurite outgrowth; established as a cue for neurodevelopment/axon guidance.	Function	[36]
1988–1990	Integrin receptor	α6β1 integrin identified as a principal Laminin receptor; foundation of Laminin–integrin axis.	Receptors/Signaling	[37]
1994	Chain nomenclature	Unified α/β/γ chain nomenclature proposed	Classification	[38]
1995	Human disease association	LAMA2 mutations cause MDC1A, linking Laminin deficiency to neuromuscular disease.	Genetics/Clinical	[39]
1999	LG domain structure	Crystal structure of LG domain clarifies dystroglycan recognition.	Structural Biology	[40]
2004	BM assembly hub	Laminin articulated as a central ‘hub’ for BM assembly.	Conceptual Advance	[41]
2005	Three-digit isoform naming	Standard Laminin isoform nomenclature (e.g., 511/521/211) established.	Standardization	[42]
2016	Glycosylation mechanism	LARGE-mediated glycan chains govern Laminin–dystroglycan binding; explains receptor inactivation in dystrophy.	Mechanism	[43]
2017	Linker proteins gene therapy	αLNNd/mini-agrin restore BM polymerization and neural function in LAMA2-deficient models.	Gene Therapy/ECM Engineering	[44]
2021	α6β1–Laminin-511 complex	Complex structure solved, enabling rational design of selective receptor modulators.	Structural Biology/Drug Design	[45]
2023–2025	Therapeutic targeting in CNS	α5-containing Laminins central to BBB maintenance, immune transmigration, neuroinflammation; elevated as therapeutic targets.	CNS/Translational	[28, 29, 46]

Structural biology and molecular diversity of the laminin family

Genetic architecture and isoform repertoire of laminin

Laminin is a heterotrimeric glycoprotein composed of one α, one β, and one γ chain that assemble through a central coiled-coil into a cruciform architecture. Five α-chain genes (LAMA1–LAMA5), three β-chain genes (LAMB1–LAMB3), and three γ-chain genes (LAMC1–LAMC3) have been identified in the human genome [47]. A β4 gene (LAMB4) also exists, although its product has not been observed to form a stable Laminin trimer [48, 49].

Although theoretical α×β×γ permutations could generate 45 combinations, strict structural compatibility between chains restricts the number of Laminins that assemble stably in mammalian tissues. According to Aumailley et al. (2005) and later analyses [42, 50], together with curated summaries [51], approximately 15 Laminin heterotrimers have been experimentally validated: Laminin-111, -121, -211, -213, -221, -311, -321, -332, -411, -421, -423, -511, -521, -522, and -523. These represent the principal Laminin isoforms identified through cloning, purification, or immunohistochemistry. Among these, several isoforms have emerged as particularly relevant for translational research. LM-411 and LM-511/521, which are enriched in vascular and neurovascular basement membranes, play key roles in angiogenesis, blood–brain barrier (BBB) integrity, and immune cell trafficking [28, 29, 52]. These isoforms are therefore increasingly studied as potential therapeutic targets in neurological and vascular disorders. Laminin isoforms display marked tissue specificity. α1-containing Laminins predominate during early embryogenesis and contribute to the formation of the earliest basement membranes [53, 54]. α2 isoforms are enriched in skeletal muscle and peripheral nerves, where they maintain mechanical stability and signaling [55]. α3 isoforms are mainly localized to epithelial basement membranes, particularly at the dermal–epidermal junction [56–60]. α4 is largely restricted to vascular endothelial basement membranes and participates in angiogenesis and permeability regulation [61]. In contrast, α5-containing Laminins are broadly distributed across epithelial and neural tissues, including BBB regions, where they regulate cell polarity and neurovascular barrier integrity [52].

Historically, Laminins were designated sequentially (e.g., “Laminin-1”), which caused ambiguity. To standardize nomenclature, Aumailley et al. introduced the widely adopted three-digit system in which the numbers denote the α/β/γ chain composition (e.g., Laminin-511 = α5β1γ1). This framework unified terminology across ECM research and facilitated interpretation of structure–function relationships and disease-associated mutations [42, 62].

Overall, Laminin gene composition and isoform diversity reflect strong evolutionary conservation coupled with functional specialization. Restricted α/β/γ combinations define tissue-specific basement-membrane architecture and support signaling integration during neurodevelopment, vascular homeostasis, and tissue repair (Fig. 1). Detailed discussions of Laminin domains and functional peptides are provided in the Supplementary File 1 and Figure S1.

Fig. 1.

Laminin isoforms of the laminin family and their tissue-specific distributions

Laminin-binding receptors and their ligand network

Laminin builds highly specific receptor networks with multiple transmembrane partners to couple mechanical adhesion with BM-to-cell signaling. Integrins were the first Laminin receptors identified; major heterodimers (α3β1, α6β1, α6β4, α7β1) are widely expressed across epithelial, neural, and muscle tissues [63, 64] and mainly recognize conserved sites within α-chain LG1–LG3 modules [50, 65]. Structural work supports a metal-ion–dependent binding mode: Arimori et al. (2021) showed that two carboxylate anchors on Laminin γ1 bridge to the β1-integrin MIDAS site, consistent with coordination between MIDAS and C-terminal Laminin residues [45]. Beyond adhesion, integrin engagement activates FAK–Src–PI3K/Akt and MAPK cascades to drive cytoskeletal remodeling, polarity, and migration [66–68]. In neural contexts (with LM-511 notably active), Laminin–integrin signaling activates Rac1/Cdc42 to promote neuritogenesis and cytoskeletal reorganization [69–71], while Laminin-dependent mechanical/receptor cues regulate YAP/TAZ to support peripheral nerve myelination and radial sorting [72, 73], together enabling neurite outgrowth and myelin formation. In muscle, α7β1 binding to Laminin-211 stabilizes the sarcolemma and transmits contractile stress; disruption yields muscular dystrophy phenotypes [74, 75]. Thus, integrin signaling exemplifies Laminin-mediated mechano-chemical coupling between structure and signaling.

Beyond integrins, dystroglycan (α-DG) forms a second core receptor system. α-DG, derived from DAG1, is heavily glycosylated; LARGE-extended O-mannosyl chains generate matriglycan that binds α-chain LG4–LG5 with high affinity [43, 76, 77]. This interaction relies on Ca²⁺ coordination and charge complementarity and sustains an ECM–cytoskeleton mechanical continuum [43]. Through β-DG, α-DG connects to the dystrophin–actin apparatus to assemble the dystrophin–glycoprotein complex (DGC), preserving tissue tension and signaling homeostasis in muscle, nerve, and the cerebrovascular system [78–80]. Impaired α-DG glycosylation or mutations at the Laminin-binding interface destabilize the Laminin–DG junction, causing myofiber detachment, synaptic disorganization, and elevated BBB permeability—hallmarks of dystroglycanopathies [81–84]. In neural tissues, α-DG co-localizes with synaptic Laminins (including α2/α5-containing isoforms) in synaptic BMs to maintain NMJ architecture and signaling plasticity [85–87].

Concurrently, basic residue–rich heparin-binding domains (HBDs) within α-chain LG4–LG5 bind HSPGs (e.g., syndecans and perlecan) to assemble ECM–growth factor composite networks [88, 89]. These HBDs sequester FGF, VEGF, and PDGF, generating local reservoirs and sharpening signaling gradients [88]; Ishihara et al. further showed that Laminin-derived HBD peptides bind multiple growth factors and enhance neovascularization and tissue repair [88]. In the neural stem-cell niche, Laminin-containing, HSPG-rich fractones stabilize FGF-2 to support proliferation and self-renewal, with perlecan required for effective FGF-2 signaling [90–93]. Consistent with this reservoir concept, Laminin HBDs display high-affinity binding to FGFs [88], and Laminin–syndecan-4 cooperation modulates migration and membrane remodeling via PKC signaling [94, 95]. Within vascular and BBB BMs, α5-containing LG4–LG5 segments provide strong heparin/HSPG-binding sites; in LG45-mediated adhesive settings, syndecans can collaborate with integrins to form composite receptor nodes. Genetic and functional evidence identifies α5 Laminins as key ECM determinants of neurovascular integrity [28, 52, 96–98].

In sum, Laminin organizes a hierarchical receptor–ligand network via three principal systems—integrins, α-DG, and HSPGs. Integrins couple mechanical linkage to intracellular signaling; dystroglycan maintains structural continuity and neuromuscular homeostasis; and HSPG complexes regulate growth-factor storage and local signal amplification. Together, this network positions Laminin as both an architect of tissue structure and a signaling hub across development, repair, and disease, providing a framework for BM disorder mechanisms and Laminin-targeted interventions (Fig. 2).

Fig. 2.

The laminin–receptor interaction network. (Illustration created with Figdraw 2.0; authorization code: SIRUU901c9)

Fundamental roles of laminin in the nervous system

Laminin in neurodevelopment and axon guidance

In early embryogenesis, the endfeet of neuroepithelial and radial glial cells adhere tightly to the BM, where Laminin furnishes a polarity- and adhesion-supportive interface and serves as a “permissive substrate” for neurite outgrowth [99, 100]. Classic functional-peptide studies first mapped bioactive motifs such as IKVAV near the distal long arm of the Laminin α-chain; at very low concentrations these motifs promote neurite extension and branching of multiple CNS/PNS neuronal types in vitro, establishing Laminin’s pro-growth role during axon initiation and elongation [101–103]. At the systems level, Laminin-rich inner limiting membrane (ILM) and the continuous retina–optic nerve BM provide a rhythmicized extracellular milieu and signaling platform for axon emergence; during RGC axon extension, sliding along BM, and selective projection at the optic chiasm, BM integrity and ECM composition critically determine path sorting (e.g., ILM/BM disruption induces axon misrouting, lamination defects, and pathway errors) [104–106]. Concurrently, integrin–Laminin adheso-mechanical coupling (FAK/Src → Rho-family GTPases) contributes to the adhesion–de-adhesion cycles of the growth cone and to actin/microtubule dynamics, thereby supplying the cytoskeletal basis for axon turning; comprehensive reviews underscore the centrality of the integrin–Laminin axis in neurite growth and guidance [70, 107–109].

At the receptor level, two adhesion–signaling modules cooperatively define Laminin’s guidance functions. (i) Integrins: Laminin-binding integrins such as α6β1, α3β1, and α7β1 recognize high-affinity sites within the α-chain LG1–LG3 modules [63, 65]. Recent structural work resolved the α6β1–LM-511 complex (E8 fragment), revealing a metal-ion–dependent coordination interface and docking to the γ-chain tail; this provides a conformational explanation for how growth cones/glia “read” Laminin cues and translate them into traction forces and downstream activation (FAK–PI3K/MAPK, Rac1/Cdc42) [110]. In the PNS, α6β1 and α7β1 on Schwann cells are indispensable for radial sorting, pre-myelinating ensheathment, and membrane spreading; their loss markedly impairs adhesion/spreading on LM-211/411, highlighting the integrin–Laminin axis as a key molecular driver of tract maturation and pre-myelination niche organization [111]. (ii) α-DG: upon matriglycan elaboration, highly glycosylated α-DG binds the LG4–LG5 modules of multiple Laminins with high affinity, and acts non–cell-autonomously during brain development as an extracellular scaffold that positions/sequesters axon-guidance cues (e.g., modulating Slit/Robo ligand distribution), thereby shaping long-range tract formation and choice across brain regions; disruption of this mechanism (e.g., glycosylation defects) causes axon pathfinding and migration abnormalities, with direct evidence in retina–visual pathway models [105, 112, 113]. Together, these findings elevate Laminin from a “passive scaffold” to an organizer of guidance signaling: via integrin-mediated traction–release cycles it controls growth-cone adhesion dynamics, and via α-DG it precisely anchors soluble/surface-bound guidance molecules where needed, sculpting trajectories in space and time during development.

Regarding isoform specificity, α5-containing Laminins (e.g., LM-511) exhibit strong adhesion and pro-neuritogenic activity across multiple neural cell lines and stem-cell systems, and are widely used as feeder-free substrates for NSC/progenitor and human iPSC maintenance/differentiation—consistent with high-affinity pairing with α6β1 and providing structural justification for E8-based applications [114–116]. By contrast, α2-containing LM-211 predominates in peripheral nerve BMs, organizing the neuromuscular endplate and myelin-related structures while furnishing mechanical support and signaling via parallel connections to integrins/α-DG. Lama2-deficient models reveal multi-level defects—from axon–glia interactions to neuromuscular connectivity—offering a pathological mirror for Laminin’s system-level roles in development and axon guidance [117–121]. In sum, Laminin orchestrates neuronal polarity, neurite dynamics, and the spatial distribution of guidance cues through a triad of mechanisms—receptor parallelism, signaling coupling, and ligand organization—a conclusion supported by convergent evidence from peptide mapping, cell biology, genetics, and structural biology (Table 2).

Table 2.

Fundamental roles of laminin in the nervous system

Item	Point of view	Reference
Neurodevelopment and axon guidance	Laminin serves as both a scaffold for polarity and adhesion and a permissive substrate for neurite extension.	[99, 100]
	The distal long arm of the laminin α-chain harbors the IKVAV motif, which—at subnanomolar concentrations—potently elicits neurite elongation and branching in both central and peripheral neurons.	[101–103]
	Laminin-rich ILM and the continuous retinal–optic-nerve BM provide a rhythmic extracellular signaling platform for axon emergence; BM integrity and ECM composition govern retinal ganglion cell axon extension, gliding, and topographic sorting at the optic chiasm.	[104–106]
	Integrin–laminin signaling, via FAK/Src→Rho-GTPase cascades, couples adhesion and mechanotransduction to orchestrate growth-cone adhesion/excursion cycles and cytoskeletal dynamics, providing the cytoskeletal basis for axonal steering and constituting a central axis in neurite outgrowth and guidance.	[70, 107–109]
	The α6β1–LM-511(E8) complex delineates a metal-ion-dependent coordination interface and docking to the γ-tail, offering a structural rationale for how growth cones decode laminin cues into traction force and downstream FAK–PI3K/MAPK and Rac1/Cdc42 activation.	[110]
	In the PNS, Schwann-cell α6β1 and α7β1 govern radial sorting, promyelinic wrapping and membrane spreading; their loss severely impairs adhesion/spreading on LM-211/411, establishing the integrin–laminin axis as a key molecular driver of bundle maturation and promyelinic niche organization.	[111]
	Hyperglycosylated α-dystroglycan, after matriglycan elongation, binds the LG4–LG5 modules of multiple laminins with high affinity and acts non-cell-autonomously as an extracellular scaffold that localizes/sequesters axon-guidance cues (e.g., Slit/Robo ligands) to pattern long-range tract selection across brain regions; disruption of this glycosylation triggers axonal path-finding and migration defects.	[105, 112, 113]
	α5-containing laminin-511 exhibits potent adhesion and neuritogenic activity, enabling feeder-free maintenance and differentiation of neural stem/progenitor and hiPSC systems; its high-affinity pairing with α6β1 provides the structural basis for E8-based substrates.	[114–116]
	Lama2-null models recapitulate hierarchical defects—from axon–glia interaction to neuromuscular junctions—providing a pathological mirror of laminin’s system-level roles in development and axon guidance.	[117–121]
Synaptogenesis and plasticity	Laminin-β2 loss misaligns presynaptic active zones with postsynaptic folds, impairs endplate differentiation, and disrupts VGCC clustering and vesicle-release coupling, establishing β2 as essential for both synaptic differentiation and active-zone organization.	[122–125]
	α5 laminin governs postsynaptic maturation at the NMJ, whereas α4 laminin maintains presynaptic-to-postsynaptic geometric alignment.	[126–128]
	The sarcoglycan complex stabilizes AChR clusters and orchestrates synaptic BM assembly; its disruption abolishes receptor aggregation and BM formation.	[129]
	Synaptic deposition of laminin-α5 by hippocampal neurons stabilizes dendritic spines and maintains synapses, marking α5-laminin as the molecular switch converting developmental plasticity to adult stability.	[130, 131]
	β2-containing laminin at photoreceptor ribbon synapses organizes active zones and maintains synapse number; β2 loss reduces central synapses and disrupts active-zone architecture, indicating that the NMJ active-zone assembly logic is conserved in the CNS.	[132]
	BM laminin acts as both a perisynaptic scaffold and a signaling hub via integrin–FAK/Src–Rho GTPase and outward receptor/channel coupling, governing receptor trafficking, vesicle cycling and local signaling gradients required for synaptic differentiation and long-term plasticity.	[131, 133–135]
	Synapse-specific laminin isoforms integrate excitation–secretion coupling, vesicle release and receptor clustering via a dual “structural anchor + receptor signaling” mode, forming an adjustable molecular module.	[122, 126, 130]
Myelination and nodes of ranvier microarchitecture	Loss of laminin γ1 or α2 impairs Schwann-cell process extension, abolishes axonal radial sorting and arrests myelination, establishing an intact BM as a structural prerequisite for initiating myelin formation.	[136, 137]
	Laminin-integrin (α6β1/α7β1) together with the sarcoglycan complex acts as a signaling hub that promotes Schwann-cell adhesion, polarization and membrane spreading while activating the FAK–PI3K–YAP/TAZ pathway to regulate myelin-membrane growth and mechanical stability.	[72, 138]
	LM-211 negatively tunes myelination by inhibiting PKA–Nrg1III signaling, thereby preserving developmental myelin homeostasis.	[139]
	Loss of dystroglycan or laminin disrupts node architecture, disperses NaV clusters and reduces conduction velocity.	[121, 140]
	Paranodal ECM—laminin, perlecan and gliomedin—partners with CAMs and microvilli to assemble an axon–glial adhesion lattice that compartmentalizes the node and secures saltatory conduction.	[141]
	LAMA2 loss simultaneously disrupts axon–glia interaction and conduction, recapitulating the combined neurological phenotype of merosin-deficient muscular dystrophy.	[118, 120]
BBB integrity and NVU homeostasis	BMECs express LM-411 and LM-511, whereas astrocytes contribute LM-211 to the parenchymal BM.	[142, 143]
	LM-411 is essential for vascular development and early barrier assembly: loss of the α4 chain causes BM defects and impaired vascular integrity.	[28]
	Lama4 deficiency leads to abnormalities in microvascular remodeling, lumen formation, and network architecture in tissues.	[144]
	Endothelial- and mural cell–derived α5 Laminins (i.e., LM-511/521) are critical for maintaining adult BBB structural integrity and function.	[52]
	Laminin-α5 deletion markedly compromises BBB stability and permeability control, revealing a spatiotemporal dual regulation by Laminin isoforms in BBB formation and homeostasis.	[28, 145]
	α6β1 integrin is a principal receptor for LM-511/521, mediating endothelial adhesion and stabilizing junctional complexes.	[45, 146]
	The Laminin α-chain LG4–LG5 module engages α-DG; biochemical mapping has identified peptide sequences within this region that interact with α-DG.	[147]
	BBB-focused reviews further note co-expression of integrins (e.g., α6β1) and the dystrophin–glycoprotein pathway in endothelial cells, suggesting a cooperative Laminin–receptor network.	[28]
	Upon complexing with ECM ligands, syndecan-4 can activate PKCα, thereby regulating endothelial migration and cytoskeletal remodeling—implicating a potential syndecan-4–Laminin → PKCα axis in post-injury endothelial migration and barrier repair.	[94, 148, 149]
	α5-containing Laminins (LM-511/521) are enriched in the endothelial BM at polarized vascular interfaces, where they stabilize cadherin/adhesion-junction architecture and suppress inflammatory leakage via integrin-dependent FAK/Src–RhoA signaling that governs cytoskeletal dynamics and junctional organization.	[150–153]
	LM-211 and LM-511 may act cooperatively in space and time to define structural boundaries and mechanical tension at the neurovascular interface.	[28, 83, 154]
	Under pathological conditions such as ischemia or inflammation, MMP-9 (and, to a lesser extent, MMP-2)–mediated Laminin degradation in the BM is a major driver of early BBB dysfunction.	[155–157]
	LM-511 substrates enhance endothelial barrier phenotypes, supporting ECM-targeted barrier improvement; the LM-511-E8 fragment is widely used for feeder-free culture of human cells and is being explored as a defined matrix for neurovascular cell systems.	[158–160]

Laminin-mediated synaptogenesis and plasticity

At the NMJ, the synaptic cleft BM is enriched in specific Laminin subunits (α4, α5, and β2) that collectively ensure precise pre-/postsynaptic alignment and maturation. Classical genetic studies show that loss of Laminin-β2 (also termed s-laminin) causes mismatching between presynaptic active zones and postsynaptic junctional folds, with endplate differentiation defects, demonstrating an indispensable role for β2 in synaptic differentiation; β2 can also bind voltage-gated calcium channels (VGCCs) to organize active-zone arrays, thereby coupling vesicle-release sites to postsynaptic architecture [122–125]. In vivo work further indicates that the α5 chain contributes to postsynaptic maturation at the NMJ (muscle-specific Lama5 deletion delays maturation), whereas α4 participates in the geometric registration and maintenance of presynaptic active zones with postsynaptic folds; these three subunits exhibit highly specific spatiotemporal enrichment and division of labor within the synaptic cleft [126–128]. At the receptor level, the dystroglycan complex not only stabilizes AChR clusters but also coordinates assembly of the synaptic BM; its impairment destabilizes AChR clustering and disrupts BM formation, underscoring a central triad—Laminin–receptor–active zone—in NMJ construction and homeostasis [129].

In the CNS, Laminin likewise directly supports chemical synapse formation and stabilization. During late development, hippocampal neurons deposit Laminin-α5 at synapses, where it is crucial for dendritic-spine structural stability and synapse maintenance, implicating α5-Laminin as a molecular hub in the transition from “developmentally dynamic” to “adult-stable” synapses [130, 131]. Separately, β2-containing Laminins at central ribbon synapses (e.g., photoreceptor synapses in the retina) have been shown to contribute to fine organization of active zones and to maintenance of synapse number; β2 deficiency reduces central synapse numbers and impairs active-zone architecture, highlighting conservation of NMJ-like “active-zone assembly” logic within the CNS [132].

From the perspective of plasticity, Laminin forms composite signaling nodes with integrins, dystroglycan, VGCCs, and HSPG/syndecan receptors, linking adhesion, ionic flux, and cytoskeletal remodeling to govern post-assembly maturation, stability, and activity-dependent remodeling of synapses. Numerous reviews conclude that the ECM—particularly BM components such as Laminins—acts not only as a “scaffold” for the perisynaptic matrix but also, via the integrin–FAK/Src–Rho GTPase axis and external coupling to receptors/channels, regulates pre-/postsynaptic differentiation and the trafficking, vesicle cycling, and local signaling gradients required for long-term plasticity (LTP/LTD) [131, 133–135]. These mechanisms echo genetic evidence at the NMJ: synapse-specific Laminin subunits integrate excitation–secretion coupling, vesicle release, receptor clustering, and subsequent stabilization through dual modes—structural anchoring and receptor-mediated signaling—yielding a tunable molecular system [122, 126, 130].

Across both NMJ and CNS, Laminin exerts key roles in synapse construction (registration, clustering, active-zone organization) and plasticity (stabilization, remodeling) via subunit-specific spatial enrichment (β2/α4/α5) and multi-receptor parallelism (integrins, dystroglycan, VGCCs, HSPG/syndecan). Loss of the relevant chains or receptors produces multi-level structural and functional defects, establishing a unified synaptic framework centered on the Laminin–receptor–active-zone/dendritic-spine axis (Table 2).

Laminin in myelination and nodes of ranvier microarchitecture

In the peripheral nervous system, Schwann cells ensheath axons to form myelin, markedly increasing conduction velocity; this process relies on tight cooperation between the cells and the basal lamina. Laminin is the core structural component of the Schwann-cell BM, with LM-211 and LM-411 as predominant isoforms. Mouse models lacking laminin γ1 or α2 exhibit impaired Schwann-cell process extension, failure of axonal radial sorting, and arrested myelination, indicating that an intact BM is a structural prerequisite for myelin initiation [136, 137]. In addition, laminin–integrin (α6β1/α7β1) and dystroglycan complexes act as signaling hubs during myelination: beyond promoting Schwann-cell adhesion, polarization, and membrane spreading, they regulate myelin membrane growth and mechanical stability by activating the FAK–PI3K–YAP/TAZ pathway [72, 138]. Notably, LM-211 can also exert negative regulation by suppressing PKA–Nrg1III signaling to prevent excessive myelination, thereby maintaining developmental myelin homeostasis [139].

Within the nodes of Ranvier formed between myelin segments, Laminin similarly builds a refined microstructural scaffold. The axolemma at nodes is enriched in voltage-gated sodium channels (Nav), whose clustering depends on spatial constraints imposed by the Schwann-cell BM and the ECM. Laminin, together with the Schwann-cell dystroglycan complex, maintains nodal structural stability: in genetic-deficit models, loss of DG or Laminin leads to nodal disorganization, dispersal of sodium-channel clusters, and reduced conduction velocity [121, 140]. Moreover, the paranodal and juxtaparanodal regions surrounding the node are rich in ECM constituents—including Laminin, perlecan, and gliomedin—which interact with CAMs (e.g., NF186, NrCAM, Contactin) and Schwann-cell microvilli to form an axon–glia adhesion network, achieving nodal compartmentalization and stable saltatory conduction [141].

Taken together, Laminin’s roles in myelination and nodal microarchitecture exemplify an integrated structure–signal–function paradigm. Laminin is both the key structural protein constructing the Schwann-cell BM and nodal scaffold, and a coordinator that, via the integrin, dystroglycan, and YAP/TAZ axes, synchronizes myelination onset, membrane stability, and the spatial organization of nodes. This multilayered regulation explains why LAMA2 deficiency (merosin-deficient muscular dystrophy) and related disorders present with concurrent axon–glia interaction defects and conduction abnormalities, underscoring the systems-level role of the Laminin network in neural development and homeostasis [118, 120] (Table 2).

Roles of laminin in BBB integrity and NVU homeostasis

The BBB is a key structure maintaining CNS homeostasis, formed by brain microvascular endothelial cells (BMECs), pericytes, astrocytic endfeet, and the intervening BM. As the physical and signaling scaffold of the NVU, the BM integrates cell adhesion, mechanical support, and signal transduction functions [161–163]. BMECs express LM-411 and LM-511, whereas astrocytes contribute LM-211 to the parenchymal BM [142, 143]. LM-411 is essential for vascular development and early barrier assembly: loss of the α4 chain causes BM defects and impaired vascular integrity [28], and Lama4 deficiency leads to abnormalities in microvascular remodeling, lumen formation, and network architecture in tissues [144]. In parallel, endothelial- and mural cell–derived α5 Laminins (i.e., LM-511/521) are critical for maintaining adult BBB structural integrity and function [52]; α5 deletion markedly compromises BBB stability and permeability control, revealing a spatiotemporal dual regulation by Laminin isoforms in BBB formation and homeostasis [28, 145].

At the molecular level, Laminin builds the foundational network for BBB adhesion and signaling through multiple receptor systems (integrins, dystroglycan, syndecans). α6β1 integrin is a principal receptor for LM-511/521, mediating endothelial adhesion and stabilizing junctional complexes [45, 146]. The Laminin α-chain LG4–LG5 module engages α-DG; biochemical mapping has identified peptide sequences within this region that interact with α-DG [147]. BBB-focused reviews further note co-expression of integrins (e.g., α6β1) and the dystrophin–glycoprotein pathway in endothelial cells, suggesting a cooperative Laminin–receptor network [28]. Although direct in vivo evidence remains limited, multiple studies indicate that upon complexing with ECM ligands, syndecan-4 can activate PKCα, thereby regulating endothelial migration and cytoskeletal remodeling—implicating a potential syndecan-4–Laminin → PKCα axis in post-injury endothelial migration and barrier repair [94, 148, 149]. Through such multi-receptor cooperativity, Laminin functions both as an adhesive scaffold and as a regulator of signaling and barrier plasticity.

At a higher organizational level, Laminin acts as a molecular nexus integrating NVU function. α5-containing Laminins (LM-511/521) are enriched in the endothelial BM at polarized vascular interfaces, where they stabilize cadherin/adhesion-junction architecture and suppress inflammatory leakage via integrin-dependent FAK/Src–RhoA signaling that governs cytoskeletal dynamics and junctional organization [150–153]. Distinct cell types deposit different Laminin isoforms at the vessel–neural interface—endothelial cells predominantly LM-411/LM-511, astrocytes mainly LM-211—creating a heterotypic ECM across BM layers. This expression pattern suggests that LM-211 and LM-511 may act cooperatively in space and time to define structural boundaries and mechanical tension at the neurovascular interface [28, 83, 154]. Under pathological conditions such as ischemia or inflammation, MMP-9 (and, to a lesser extent, MMP-2)–mediated Laminin degradation in the BM is a major driver of early BBB dysfunction [155–157]. In vitro BBB models show that LM-511 substrates enhance endothelial barrier phenotypes (elevated TEER, stabilized junctional proteins), supporting ECM-targeted barrier improvement; the LM-511-E8 fragment is widely used for feeder-free culture of human cells and is being explored as a defined matrix for neurovascular cell systems [158–160]. Thus, the spatiotemporal distribution of Laminin and its receptor networks not only determines BBB morpho-homeostasis but also provides a molecular framework for understanding NVU barrier function and pathological plasticity (Table 2).

Laminin: disease associations and mechanisms

Roles of laminin in IS

IS results from arterial occlusion or critical stenosis that interrupts local cerebral blood flow and glucose–oxygen supply, leading to neuronal injury and necrosis [164–166]; it accounts for approximately 80–90% of all strokes [167]. Etiologies include cerebral thrombosis, embolism, and small-vessel disease, and the condition often leaves severe sequelae such as hemiparesis, aphasia, sensory deficits, and cognitive decline, with high incidence, disability, and recurrence rates [168]. Global burden analyses indicate that IS is among the leading causes of death and disability worldwide, imposing substantial public-health and socioeconomic burdens [169]. Mechanistically, disturbances in energy metabolism, oxidative stress, excitotoxicity, inflammatory responses, apoptosis, and BBB disruption are tightly coupled, with BBB injury recognized as a key driver of cerebral edema, inflammatory spread, and neurological deterioration [165, 170, 171].

During early ischemia and reperfusion, rapid activation of the matrix metalloproteinases MMP-9/MMP-2 directly degrades core components of the BBB BM—laminin and type IV collagen—precipitating barrier rupture, vasogenic edema, and hemorrhagic transformation [156, 172, 173]. Consistent with this, laminin expression exhibits temporal dynamics after stroke: in the acute phase (hours to ~ 1 day) immunoreactivity in the infarct core declines sharply, indicating early ECM degradation; during reperfusion the BM is rapidly compromised (an effect partly mitigated by hyperbaric oxygen); in the subacute/chronic phases, astrocytic laminin becomes reactively upregulated and redeposited, marking initiation of NVU reconstruction and ECM repair. Additional evidence includes: Nirwane et al. showed that pericyte-derived laminin-α5 aggravates ischemic injury [174]; Horstmann et al. observed increases in MMP-2/9 with concomitant decreases in intact laminin and TIMP-2 during ischemia, with MMP-9 and laminin levels varying with infarct volume and treatment [175]; at the clinical/review level, serum netrin-1 (a laminin-related neurovascular protective protein) shows relevant associations [176], while permanent vascular injury correlates with upregulation of laminin β/γ chains and transient injury with downregulation of α chains [30]; furthermore, Alam et al. reported increased MMP-2/9 with significant degradation of laminin and type IV collagen in the ischemic hemisphere (p < 0.001) [177], and single-cell transcriptomics suggests enhanced laminin-related signaling post-stroke [178]. In the repair phase, laminin-α2 promotes OPC differentiation and myelin-protein expression [179]; Bios et al. found that a recombinant human BM proteoglycan laminin-like globular domain 3 (rhPDV-LG3) confers neuroprotection and functional improvement in experimental IS [180]; porous laminin-rich materials loaded with VEGF markedly enhance angiogenesis [181], and treadmill exercise fosters recovery by upregulating VEGF and laminin and increasing microvascular density [182].

These insights support a two-pronged therapeutic concept of “inhibit early degradation—promote later reconstruction.” In rodent models, the selective gelatinase inhibitor SB-3CT attenuates proteolysis of BM laminin, alleviating BBB injury and edema; combined with delayed tPA, it extends the effective thrombolysis window to ~ 6 h post-ischemia and affords significant neuroprotection [155–157, 183]. Beyond protease inhibition, multi-target interventions also align with laminin preservation or restoration: e.g., GuHong injection and Qishen Yiqi improve inflammation and neuronal survival while elevating/improving laminin expression [184, 185]; intracerebral transplantation of human bone-marrow stromal cells (SB623) plus voluntary exercise expands laminin-positive areas in the SVZ and DG and improves function [186]; the CO-releasing molecule CORM-3 upregulates laminin and downregulates MMP-9, providing prophylactic protection [187]; in OGD/R co-treatment models, Danshen–Chuanxiong reduces ROS and enhances laminin/type IV collagen [188]; chlorpromazine + promethazine suppress AQP-4/9 and MMP-2/9 increases while reversing tight-junction and laminin loss [189]; low-dose candesartan augments MMP-3, laminin, and Ang-1 to promote plasticity [190]; MDL 28,170 improves neurological function, elevates laminin, collagen IV, and occludin, and mitigates NVU ultrastructural damage [191]; with tPA, addition of T541 dose-dependently attenuates laminin downregulation in the ischemic hemisphere [192]; and highly specific MMP-9 inhibition spares laminin from proteolysis in tMCAO and reduces neuronal apoptosis [155].

Overall, the disabling nature and complex pathobiology of IS underscore that “time is brain,” with MMP-2/9–mediated early BM degradation, time-dependent laminin remodeling, and NVU repair forming a critical continuum from acute injury to tissue reconstruction. Targeting the laminin/BM–MMP axis offers a composite strategy that may both curb early BBB breakdown and accelerate later revascularization and remyelination, highlighting its potential for translational application (Fig. 3 and Table 3).

Fig. 3.

Roles and functions of laminin in IS. (Illustration created with Figdraw 2.0; authorization code: YWIUYe1101)

Table 3.

The role of laminin in major nervous system diseases

Disease	Point of view	Reference
IS	In the early phase of ischemia-reperfusion, rapidly activated matrix MMP-9/2 directly degrades the core components of the BM—laminin and type IV collagen—thereby inducing BBB disruption, vasogenic edema, and hemorrhagic transformation.	[156, 172, 173]
	Pericyte-derived laminin-α5 exacerbates ischemic injury.	[174]
	During ischemia, MMP-2/9 elevation parallels losses of intact laminin and TIMP-2, with their levels dynamically tracking infarct volume and therapeutic intervention.	[175]
	Serum netrin-1—a laminin-related neurovascular protective protein—shows significant clinical correlations.	[176]
	Persistent vascular injury is linked to up-regulation of laminin β/γ chains, whereas transient injury associates with down-regulation of the α chain.	[30]
	In the ischemic hemisphere, elevated MMP-2/9 coincides with pronounced degradation of laminin and type IV collagen.	[177]
	Single-cell transcriptomics further reveals post-stroke up-regulation of laminin-related signaling.	[178]
	During repair, laminin-α2 drives oligodendrocyte precursor cell differentiation and myelin-protein expression.	[179]
	Recombinant human BM proteoglycan laminin-like globular domain 3 (rhPDV-LG3) exerts neuroprotective and function-enhancing effects in experimental ischemic stroke.	[180]
	VEGF-loaded porous laminin-rich scaffolds significantly enhance angiogenesis.	[181]
	Treadmill training promotes recovery by upregulating VEGF and laminin and increasing microvascular density.	[182]
	The selective gelatinase inhibitor SB-3CT preserves basal-lamina laminin, attenuates BBB injury and edema, and extends the thrombolytic window to ~6 h when combined with delayed tPA, yielding robust neuroprotection.	[155–157, 183]
	GuHong injection and Qishen Yiqi formula simultaneously attenuate inflammation, enhance neuronal survival, and up-regulate laminin expression.	[184, 185]
	Combined intracerebral SB623 transplantation and voluntary exercise expands laminin-positive territories in the SVZ and DG, promoting functional recovery.	[186]
	The CO-releasing molecule CORM-3 upregulates laminin and downregulates MMP-9, conferring prophylactic protection.	[187]
	In OGD/R co-treatment models, the Danshen–Chuanxiong combination reduces ROS while enhancing laminin and type IV collagen.	[188]
	Chlorpromazine plus promethazine suppresses up-regulation of AQP-4/9 and MMP-2/9 and simultaneously reverses the loss of tight-junction proteins and laminin.	[189]
	Candesartan augments MMP-3, laminin, and Ang-1 to foster post-injury plasticity.	[190]
	MDL 28,170 improves neurological function, elevates laminin, collagen IV and occludin, and mitigates NVU ultrastructural damage.	[191]
	tPA combined with T541 dose-dependently attenuates laminin down-regulation in the ischemic hemisphere.	[192]
	Highly specific MMP-9 inhibition prevents laminin proteolysis and reduces neuronal apoptosis in tMCAO.	[155]
HS	Damage to the blood–brain barrier and its microvascular BM—composed chiefly of type IV collagen and laminin—is a key driver of secondary injury.	[193–195]
	Post-hemorrhage, MMP-9 surges to degrade the BM, heighten permeability, and worsen edema plus neurological decline.	[196]
	Ablation of astrocyte-derived laminin impairs vascular smooth-muscle cell function and predisposes to hemorrhage.	[197]
	Endothelial laminin-α5 deficiency aggravates tissue injury and neurological impairment after ICH.	[145]
	Perivascular-cell-derived laminin protects by down-regulating caveolin-1 and curbing excessive endocytosis, thereby preserving the BBB and stabilizing cerebral water homeostasis.	[198]
	Cilostazol prevents collagenase-induced endothelial death and preserves type IV collagen, laminin, and VE-/N-cadherin, thereby attenuating BBB disruption in ICH models.	[199]
VCI	NXP031 up-regulates BM laminin, endothelial, and pericyte markers, preserves BBB integrity, and ameliorates chronic-hypoperfusion-induced cognitive deficits; its successor NXP032 attenuates microvascular fragmentation, modulates PDGFR-β/ZO-1/laminin expression, suppresses astrocyte/microglial activation, and mitigates neurovascular aging and cognitive decline in aged mice.	[200, 201]
	G-CSF improves cognition by restoring vascular and perivascular architecture via increasing VEGF and BrdU+ /laminin+ endothelial cells while down-regulating MMP-9.	[202]
	Within the pathogenic cascade of chronic hypoperfusion → BBB injury → white-matter damage, BM laminin serves as the key ECM cue for barrier maintenance and reconstruction.	[203, 204]
AD	In AD, laminin—together with type IV collagen, nidogen, and heparan-sulfate proteoglycans—builds a 3-D BM lattice that stabilizes the BBB and the endothelium–pericyte–astrocytic endfoot unit.	[20, 205]
	In CAA regions, capillary/arteriolar BM laminin is replaced by or markedly depleted owing to Aβ deposition, mirroring local BM abnormalities and lesion progression.	[206, 207]
	Laminin binds Aβ/APP with high affinity and curbs fibril formation in vitro; its 37/67-kDa receptor mediates Aβ cytotoxicity and aberrant APP processing, while BM genes like LAMB2 emerge as biomarkers—positioning a “laminin axis” at multiple AD pathogenic nodes.	[208–212]
	Region-specific up-regulation of α1 and γ1 laminin chains denotes domain-restricted functional contributions to AD pathophysiology.	[213]
	The 37/67-kDa laminin receptor has emerged as an AD therapeutic target, spawning small-molecule inhibitors and associated patents.	[214, 215]
	The 37/67-kDa laminin receptor mediates Aβ endocytosis, directly engages PSEN1 and indirectly couples to BACE1 to steer APP processing; the small-molecule inhibitor NSC47924 reprograms APP trafficking, dampens aberrant Akt–mTOR signaling and activates autophagy, culminating in reduced Aβ burden.	[216, 217]
	In familial AD cellular models, antagonism of the 37/67-kDa laminin receptor rescues APP maturation and lowers Aβ production.	[211]
	LRP:FLAG-mediated knockdown of phosphorylated tau broadens the laminin–endocytosis–autophagy/proteostasis therapeutic paradigm.	[218]
	LM-511 suppresses apoptosis and excitotoxicity while stabilizing synapses, and its loss produces behavioral deficits; aberrant Aβ–α5-laminin interactions physically obstruct neuronal receptor docking and inhibitory signaling, triggering neuronal dysfunction.	[219]
	In AD brains, BM laminin is fragmented and co-localizes with Aβ plaques.	[220]
	Laminin possesses anti-amyloidogenic properties.	[221]
	An expanded LAMA2+ oligodendrocyte subset is present in AD tissue.	[222]
	AD plasma significantly increases laminin-dependent and lectin-EC migration length along microcontact-printed tracks, and the laminin-related netrin-1/UNC5C axis participates in disease regulation.	[223, 224]
PD	Laminin is a core constituent of the nigrostriatal BM, directly governing midbrain dopaminergic neuron survival, differentiation, and axonal outgrowth.	[203, 225]
	LM-511 markedly promotes midbrain dopaminergic neuron survival and differentiation via YAP-related signaling.	[226]
	LM511-E8 has been employed as a feeder-free matrix for generating clinical-grade dopaminergic progenitors.	[227–229]
	Pre-treating dopaminergic progenitors with perlecan-conjugated laminin-E8 or the IKVAV peptide accelerates graft maturation and neurite outgrowth, confirming ECM cues as instructive signals for the regenerative niche.	[103, 230–233]
	Netrin-1 deletion triggers mDA apoptosis via UNC5B-mediated MST1 activation, underscoring the essential role of the laminin-like secreted-protein axis in dopaminergic homeostasis.	[234]
	Peripheral biomarker studies in PD have consistently linked LAMB2 to disease risk.	[235]
	In the 6-OHDA rat model, T-cell depletion exacerbates behavioral deficits and coincides with reduced brain laminin levels.	[236]
	The KDI tripeptide derived from γ1-laminin protects dopaminergic neurons against toxic injury.	[237]
	Chronic cervical spinal cord stimulation attenuates microglial activation, expands cortical laminin-positive areas, and improves motor behavior in experimental PD.	[238–240]
	Collagen/laminin tubular hydrogel (TE-NSP) encapsulating aggregated dopaminergic neurons and axon bundles reduces host neuronal loss and inflammation and survives long-term in brain; VEGF gene transfer affords neuroprotection by increasing laminin-positive vascular density.	[241, 242]
	Laminin-peptide-grafted collagen hydrogel boosts grafted neural stem-cell survival, while NT3-loaded, laminin-coated pharmacologically active microcarriers combined with dopaminergic induced cells enhance behavioral outcomes and protect/repair the nigrostriatal pathway.	[243–245]
ALS	Laminin—particularly the β2 and α4 chains—directly governs the structural and functional homeostasis of the neuromuscular junction.	[86]
	Loss of laminin-β2 disrupts presynaptic active-zone formation and differentiation, reduces end-plate potential frequency, and compromises neuromuscular transmission.	[246]
	Laminin-α4 loss disrupts active-zone–postsynaptic-fold alignment, producing a “premature-aging” NMJ phenotype and highlighting its essential role in adult NMJ maintenance.	[127, 247]
	NMJ morphological abnormalities emerge early in ALS, yet extraocular muscles resist denervation through a distinctive laminin isoform repertoire, indicating that modulating synaptic laminins can bolster NMJ resilience.	[248–250]
	NMJ homeostasis requires synergistic action of synaptic laminin and the agrin–LRP4–MuSK pathway, highlighting the therapeutic potential of the laminin–agrin–LRP4/MuSK axis in ALS.	[251, 252]
	Elevated laminin-1 expression has been observed in ALS skin.	[253]
	γ1-laminin is selectively overexpressed by reactive astrocytes and distributed across cervical/thoracic tracts in ALS spinal cord.	[254]
	In ALS, limb-muscle BM shows reduced laminin α2/β2 and loss of α4, whereas extraocular muscle displays a distinct profile.	[255]
	Studies report no significant change in overall laminin levels in ALS patients, reflecting isoform- and stage-specific differences as well as sample heterogeneity.	[256]
	In ALS temporal models, γ1-laminin increases with disease progression.	[257]
	Targeting the blood–spinal cord barrier with human bone-marrow endothelial progenitor cell transplantation reinforces “dense BM” laminin immunoreactivity and restores barrier integrity, providing experimental support for ECM/BM-protective strategies.	[258]
MS	LM-511 fortifies endothelial junctions and curbs extravasation, whereas LM-411-rich segments readily serve as leukocyte portals, so BBB laminin composition directly governs inflammatory infiltration and lesion formation.	[28, 259, 260]
	Active MS lesions exhibit loss of vascular and astrocytic BM laminin alongside ECM remodeling and altered integrin profiles; patients’ lymphocytes show enhanced laminin-degrading capacity correlating with disease activity, implicating protease-mediated BM breakdown in BBB destabilization.	[261–264]
	During remyelination, vessel- and axon-aligned laminin provides adhesive tracks and integrin–Fyn/FAK cues that drive OPC migration, survival, and differentiation; LM-211/411/511 and their E8 fragments potentiate these responses, directly coupling ECM imbalance to repair failure.	[265–268]
	Rare/low-frequency variants implicate LAMA5 and LAMB1 in multiple sclerosis susceptibility.	[269]
	LAMA2-related muscular dystrophy can present with an MS-like phenotype.	[270]
	Loss of NG2 in OPCs/pericytes depletes BM molecules, including laminins and collagens IV/VI.	[271]
	Down-regulation or decoupling of endothelial β1/VLA-6 from laminin facilitates leukocyte transit.	[262]
	The MCAM–LM-411 axis facilitates TH17 cell entry into the CNS.	[272, 273]
	Perivascular cuffs are enriched for multiple laminin isoforms and other ECM components.	[274]
	Network and mechanobiology analyses position LAMA1 as a nodal hub within MS lesion networks.	[275]
	Tissue stiffening correlates with inflammatory infiltration and increased laminin content.	[276]
	Chronic-phase expression of dystrophin and laminin declines.	[277]
	High Treg motility on laminin substrates and cortical Lama4/5 up-regulation reveal an immune–BM–mechanics coupling.	[278, 279]
	Natalizumab lowers MMPs and raises TIMPs during peak and chronic phases, curbing BM laminin degradation and inflammatory infiltration.	[280]
	Berberine confers neuroprotection by inhibiting gelatinases and reducing laminin degradation, offering pharmacological validation for ECM-protective strategies.	[281]
Depression	Chronic stress downregulates hippocampal and frontal laminin, an effect partially reversed by antidepressants, implicating ECM/laminin in stress–depression plasticity.	[282, 283]
	Region-specific manipulation of LAMB1 in mice alters anxiety-/depression-like behaviors and pain sensitization, supporting a functional role for laminin in affective regulation.	[284]
	Antidepressants induce hippocampal vascular remodeling marked by increased laminin and CD31 sprouting.	[285]
	tPA/plasmin degrades laminin, sensitizing hippocampal neurons to injury and indicating that stress-linked proteolysis undermines plasticity and survival by disrupting the ECM–laminin axis.	[286]
	EGFLAM—which encodes EGF-like, fibronectin type III, and laminin G domains—shows genome-wide significant association with cortical silent period in patients with depression.	[287]
	The 67-kDa laminin receptor is down-regulated in olfactory epithelial neural progenitors from patients with major depressive disorder or borderline personality disorder.	[288]
	Adamts18 knockout mice exhibit reduced depression-like behavior and increased neurite outgrowth, potentially via activation of the laminin/PI3K/AKT/GSK-3β pathway.	[289]
	LAMA5 has been proposed as a potential biomarker for concomitant myocardial hypertrophy and cardiac dysfunction in patients with depression.	[290]
	Laminin levels are reduced in the parieto-occipital cortex of depressed patients.	[291]
	An interaction between LAMA2 and illness duration influences the thickness of the right Heschl’s gyrus.	[292]
	Norepinephrine up-regulates neuronal sprouting/differentiation-related genes, including laminin.	[293]
	In chronic-stress rats, 3,6′-disinapoyl sucrose reverses anhedonia and CAM-L1/laminin/BDNF down-regulation, identifying membrane protection/ECM remodeling as a novel antidepressant strategy.	[294]
Anxiety	Selective LAMB1 downregulation in the mouse ACC induces anxiety-/depression-like behaviors and synaptic-circuit dysfunction, which are reversed by LAMB1 restoration.	[284]
	Aberrant laminin/integrin signaling weakens endothelial junctions and amplifies neuroinflammation, driving anxiety-related symptoms.	[28, 98]
	Laminin signaling and its bioactive fragments promote neurite outgrowth and circuit remodeling, pointing to ECM protection/reconstruction as a novel therapeutic avenue.	[101]
	RA/RARβ transcriptionally tunes LAMB1 to restore ECM homeostasis, normalize synaptic plasticity, and alleviate neuropathic pain and aversive affect, validating the RA–LAMB1–ECM/plasticity axis as a therapeutic target for anxiety and comorbid pain-related anxiety.	[295]
TBI	Early MMP-9 up-regulation proteolyzes BM laminin, disrupts the BBB and triggers inflammation/edema, followed by peri-lesional laminin re-expression that recapitulates an “acute loss → subacute remodeling” sequence.	[21, 296–298]
	In the controlled cortical impact model, laminin and fibronectin are significantly elevated in the pericontusional penumbra from day 3 to day 14, contributing to barrier repair and gliosis regulation.	[299]
	Changes in laminin occur synchronously with BBB structural integrity and correlate with permeability defects in TBI/cerebral hemorrhage.	[30]
	TBI triggers neurovascular unit remodeling and highlights the BM–laminin axis as a pivotal guardian of microenvironmental homeostasis.	[300]
	Extracerebrally, contralateral limb muscle shows upregulation of laminin and type IV collagen.	[301]
	Post-traumatic cerebrovascular dystrophin loss couples with altered vascular laminin immunoreactivity.	[302]
	Laminin-based scaffolds enhance the survival and integration of neural stem cells within injured brain tissue.	[303]
	Self-assembling peptide hydrogels presenting IKVAV or engineered RADA16 suppress acute apoptosis and inflammation, potentiate neurite outgrowth, and improve functional outcomes in TBI/ICH models.	[31, 304, 305]
	IKVAV-based bioactive peptides were tailored for TBI applications.	[306]
	A laminin-coated electronic scaffold with vascular topology was specifically engineered for traumatic brain injury.	[307]
	An anti-inflammatory multicomponent hydrogel incorporating Fmoc-DIKVAV and fucoidan was designed for traumatic brain injury.	[308]
	For TBI, an IKVAV-nanoscaffold enabling engraftment of human meningioma stem cells was designed.	[309]
	A hyaluronan–laminin hydrogel that amplifies SDF-1α-directed chemotaxis and graft integration was devised for TBI.	[310]
	Valproate plus fresh-frozen plasma restores BBB integrity and upregulates laminin in TBI complicated by hemorrhagic shock.	[311]
	Large-animal exosome therapy fortifies neuroprotection and BBB function, elevating laminin, claudins, and ZO-1.	[312]
	The PARP inhibitor PJ34 suppresses MMP-9 while upregulating claudins, laminin, collagen IV, and integrin β1, thereby reducing contusion volume and neurological deficits.	[313]

Roles of laminin in HS

HS is primarily classified into intracerebral hemorrhage (ICH) and aneurysmal subarachnoid hemorrhage (aSAH). In both entities, rupture of intracranial vessels leads to extravasation of blood into the brain parenchyma or the subarachnoid space, causing increased intracranial pressure, hematoma formation, and toxicity from blood breakdown products, and triggering cascades of inflammatory responses—collectively yielding poor outcomes. Guidelines and reviews concur that ICH is the most fatal form of acute stroke, with early case-fatality rates of approximately 30–40% and limited improvement to date; although the age-standardized global burden of aSAH has declined in recent years, it still accounted for hundreds of thousands of new cases in 2021 with high mortality and disability, underscoring the need for rapid diagnosis, early aneurysm securing, and intensive care management [314, 315].

Pathophysiologically, injury to the BBB and its microvascular BM—composed chiefly of type IV collagen and laminin—is a key driver of secondary damage [193–195]: post-hemorrhage, matrix metalloproteinases (especially MMP-9) are rapidly upregulated, promoting BM degradation and increased permeability, thereby exacerbating cerebral edema and neurological deterioration [196]. As a BM hub protein, laminin is therefore essential for maintaining BBB structure and NVU stability.

Multiple experimental studies reinforce this concept: ablation of astrocyte-derived laminin impairs vascular smooth-muscle cell function and predisposes to hemorrhage [197]; endothelial laminin-α5 deficiency aggravates tissue injury and neurological impairment after ICH (larger lesion volumes, heightened BBB permeability, increased inflammatory infiltration and gliosis) [145]; conversely, perivascular cell–derived laminin protects by downregulating caveolin-1 and suppressing excessive endocytosis, thereby mitigating BBB damage and regulating brain water homeostasis in ICH [198]. Pharmacologically, cilostazol can prevent endothelial cell death and protect type IV collagen, laminin, vascular endothelial cadherins, and neural cadherins from collagenase-induced injury, ameliorating BBB disruption in collagenase models of ICH. Collectively, these data highlight the laminin–BM–protease axis as central to secondary injury in hemorrhagic stroke and as a promising therapeutic entry point [199] (Fig. 4 and Table 3).

Fig. 4.

Roles and functions of laminin in HS. (Illustration created with Figdraw 2.0; authorization code: PYYOTa61a6)

Roles of laminin in VCI

VCI comprises a spectrum of cognitive deficits caused by cerebrovascular pathology, ranging from mild cognitive decline to vascular dementia [316]. Small-vessel disease is the most common subtype (e.g., white-matter hyperintensities, lacunes, microbleeds) and is a major source and accelerator of post-stroke and late-life cognitive decline. Recent reviews and consensus statements indicate that the core pathology of VCI/VCID includes chronic hypoperfusion, endothelial dysfunction, and BBB leakage, accompanied by neuroinflammation, oxidative stress, and white-matter demyelination; clinically, executive dysfunction and slowed processing speed predominate, and assessment/follow-up can reference the standardized NINDS–CSN procedures and scales [317–320].

Mechanistically, convergent imaging and fluid/pathologic evidence suggests that BBB dysfunction is likely an early driver of small-vessel disease and VCI: BBB leakage and increased “free water” in brain tissue correlate with worse cognitive performance, directly linking microvascular/white-matter microenvironment injury to cognitive decline [321, 322]. In line with this critical node, laminin—a core extracellular-matrix component of the cerebral microvascular BM—is considered a determinant of endothelial barrier phenotype and of adhesion/signaling among pericytes, astrocytic endfeet, and endothelium. Multiple studies suggest isoform-specific, “instructive” roles of Laminins in BBB stabilization and repair; thus, protection or reconstruction of the Laminin–BM axis is emerging as a potential therapeutic direction for VCI/small-vessel disease [20, 28].

Translational efforts are advancing along these lines: Li et al. reported that NXP031 upregulates BM (Laminin), endothelial (RECA-1, PECAM-1), and pericyte (PDGFRβ) markers, preserves BBB integrity, and improves chronic hypoperfusion–induced, VD-like cognitive deficits in rats; they subsequently developed NXP032, which mitigates microvascular fragmentation and modulates PDGFR-β, ZO-1, and Laminin expression while dampening astrocyte/microglial activation, thereby ameliorating neurovascular aging and cognition in aged mice [200, 201]. Tuo et al. showed that G-CSF improves cognition by repairing vascular endothelium and perivascular structures—via increased VEGF and BrdU⁺ /Laminin⁺ endothelial cells and downregulation of MMP-9 [202]. Reviews further note serum protein extravasation (indicative of BBB leakage) in VCI brain tissue, elevated CSF albumin and Laminin, and imaging evidence consistent with increased BBB permeability. Along the pathogenic cascade of “chronic hypoperfusion → BBB injury → white-matter damage,” BM-Laminin represents a key ECM cue for barrier maintenance/reconstitution, and combined strategies that inhibit proteases—protect the BM (including Laminin)—and promote repair appear feasible with translational potential [203, 204] (Fig. 5 and Table 3).

Fig. 5.

Roles and functions of laminin in VCI. (Illustration created with Figdraw 2.0; authorization code: WUSOIaa637)

Roles of laminin in AD

AD is a neurodegenerative disorder characterized by progressive decline in memory and cognition [323]. Under the NIA–AA research framework, AD is biologically defined as an 〔AT(N)〕 continuum centered on β-amyloid (Aβ) deposition, tau pathology, and neurodegeneration, with clinical symptoms viewed as phenotypic expressions of this biological process [7]. The societal impact stems from high prevalence and substantial caregiving burden: the global number of people living with dementia is projected to rise from ~57.4 million in 2019 to ~153 million by 2050; in the United States alone, caregiving time and economic costs related to AD remain substantial in 2024 [324, 325]. On the therapeutic front, disease-modifying approaches have made incremental progress: the anti-Aβ monoclonal antibody lecanemab significantly clears amyloid and “moderately slows” cognitive/functional decline over 18 months in early AD, and donanemab received FDA approval in 2024 for early symptomatic AD, reflecting the growing adoption of biomarker-stratified clinical trial strategies [326, 327]. In parallel, the Lancet Commission on dementia prevention, intervention and care (2024 update) added “uncorrected vision loss” and “high LDL cholesterol” as modifiable risk factors, emphasizing life-course, multifactorial management to delay or reduce a substantial proportion of dementia cases [328].

In AD, laminin is a core constituent of the cerebral microvascular BM [205], which—together with type IV collagen, nidogen, and heparan-sulfate proteoglycans—forms a 3D network that maintains the BBB and the coordinated stability of the endothelium–pericyte–astrocytic endfoot unit [20]. The BM is also a major pathway for intramural periarterial drainage (IPAD) of Aβ from the brain; with aging and AD progression, BM composition and biomechanics remodel, correlating with impaired clearance and vessel-wall Aβ deposition (cerebral amyloid angiopathy, CAA) [329, 330]. Human and animal studies indicate that in CAA regions, capillary/arteriolar BM laminin can be replaced by—or markedly reduced due to—Aβ deposition, consistent with local BM abnormalities and lesion progression [206, 207]. Moreover, laminin binds Aβ/APP with high affinity and can inhibit Aβ fibrillization in vitro; the 37/67-kDa laminin receptor interacts with Aβ and has been implicated in Aβ cytotoxicity and aberrant APP processing, while BM-related genes (e.g., LAMB2) have been proposed as potential biomarkers—positioning a “laminin axis” at several key nodes of AD pathogenesis [208–212]. Palu et al. further observed heightened, regionally specific expression patterns of α1 and γ1 laminin, suggesting domain-specific functional contributions to AD pathophysiology [213].

Evidence surrounding the 37/67-kDa laminin receptor (LRP/LR) has steadily accumulated: early proposals nominated it as a candidate therapeutic target in AD [214], followed by small-molecule inhibitory strategies and related patents [215]. Mechanistically, this receptor has been reported to mediate Aβ endocytosis, directly interact with the γ-secretase subunit PSEN1, and associate indirectly with BACE1, thereby influencing APP sorting and processing; small-molecule inhibitors (e.g., NSC47924) can remodel APP maturation/endocytosis, downregulate aberrant Akt–mTOR signaling, and activate autophagy, ultimately reducing Aβ burden [216, 217]. In familial AD cell models, inhibiting this receptor rescues APP maturation and decreases Aβ generation [211]; other work suggests that LRP:FLAG manipulations can reduce phosphorylated tau, broadening the laminin—endocytosis—autophagy/proteostasis therapeutic concept [218].

Broader laminin-related findings point to both vascular and neuronal dimensions: LM-511 appears to protect neurons from apoptosis, suppress excitotoxicity, and stabilize dendritic spines/synapses; loss of its signaling produces behavioral deficits. Abnormal interactions between Aβ and α5-laminin may physically hinder docking of neuronal membrane receptors and inhibitory signaling, potentially driving neuronal dysfunction [219]. Histopathologically, AD tissue shows BM-laminin fragmentation co-localizing with Aβ plaques [220]; in vitro, laminin demonstrates anti-amyloidogenic properties [221]. Multi-omics and functional studies further report expansion of LAMA2⁺ oligodendrocyte subsets in AD tissue, AD plasma–induced enhancement of laminin-dependent and lectin-EC migration length along microcontact-printed tracks [222, 223], and involvement of the laminin-related netrin-1/UNC5C axis in disease modulation (UNC5C fragments accelerating AD pathology, with knockout partially rescuing cognition) [224]. Taken together, strategies centered on BM-laminin structural maintenance/reconstruction, promotion of perivascular clearance, targeting laminin–Aβ interactions, and modulating 37/67-kDa receptor–mediated endocytosis–autophagy–APP/tau pathways constitute promising therapeutic directions for AD and CAA (Fig. 6 and Table 3). Overall, current evidence supports a potentially relevant role for laminin in AD-related vascular dysfunction, Aβ handling, and synaptic stability; however, compared with stroke or BBB-centered disorders, the mechanistic chain remains less complete, and much of the evidence is still associative or preclinical.

Fig. 6.

Roles and functions of laminin in AD. (Illustration created with Figdraw 2.0; authorization code: YTSIW23adb)

Roles of laminin in PD

PD is a progressive neurodegenerative disorder characterized pathologically by loss of dopaminergic neurons in the substantia nigra pars compacta and misfolded α-synuclein deposition (Lewy bodies/neurites). Beyond the cardinal motor features—bradykinesia, rigidity, resting tremor, and postural–gait disturbances—PD presents with diverse non-motor symptoms including hyposmia, constipation, sleep disturbance, mood changes, and autonomic dysfunction, many of which can precede motor onset by years [331]. With global population aging, the prevalence and disability burden of PD continue to rise, imposing substantial medical and socioeconomic pressures on individuals and care systems. Current treatments are largely symptomatic (levodopa, dopamine agonists, MAO-B inhibitors, etc.); medication fluctuations or refractory tremor can be effectively and durably addressed with deep brain stimulation (DBS), but no disease-modifying therapy has yet been established [332, 333].

In PD, laminin is a key extracellular-matrix component of the basal lamina and the microenvironment of the nigrostriatal pathway, directly influencing the survival, differentiation, and axonal growth of midbrain dopaminergic (mDA) neurons [203, 225]. Basic studies show that LM-511 markedly promotes mDA neuron survival and differentiation (implicating YAP and related pathways) [226]. In stem-cell and transplantation workflows, LM511-E8 has been incorporated as a feeder-free matrix for manufacturing clinical-grade dopaminergic progenitors [227–229]. In grafting strategies, pretreating dopaminergic progenitors with perlecan-conjugated laminin-E8 fragments enhances graft maturation, neurite extension, and functional outcomes; laminin-derived peptides (e.g., IKVAV) likewise promote neural progenitor adhesion and neuritogenesis, indicating that ECM cues can serve as “instructive signals” for a regenerative niche [103, 230–233]. In addition, loss of netrin-1 triggers mDA apoptosis via UNC5B-mediated activation of MST1, further underscoring the importance of “laminin-like” secreted-protein axes for dopaminergic system homeostasis [234].

Multi-level evidence links laminin to disease stratification and the immune microenvironment. In peripheral biomarker studies of sporadic PD, LAMB2 has shown reproducible risk associations [235]. In the 6-OHDA rat model, T-cell deficiency not only worsens behavioral deficits but is accompanied by decreased brain laminin content [236]; conversely, the KDI tripeptide derived from γ1-laminin protects dopaminergic neurons against toxic injury [237]. These findings suggest that a laminin-centered BM/ECM axis participates in neuronal maintenance and may furnish intervention points coupling biomarkers with immune–regenerative modulation.

Broader reparative and engineering avenues also converge on laminin. Peptidic nanofibers mimicking heparan sulfate and laminin reduce striatal injury and promote functional recovery; chronic cervical spinal cord stimulation in experimental PD decreases microglial activation, increases cortical laminin-positive areas, and improves behavior [238–240]. In tissue engineering, collagen/laminin tubular hydrogels encapsulating aggregated dopaminergic neurons and axon bundles (TE-NSP) reduce host neuronal loss and inflammation and survive long-term in the brain; VEGF gene transfer confers neuroprotection by increasing laminin-positive vascular density [241, 242]. Laminin-peptide–modified collagen hydrogels significantly improve survival of transplanted neural stem cells, and laminin-coated, NT3-releasing pharmacologically active microcarriers combined with dopaminergic induced cells enhance behavioral outcomes and protect/repair the nigrostriatal pathway [243–245]. Collectively, strategies spanning maintenance/reconstruction of the BM–laminin architecture, optimization of the cell-graft microenvironment, and development of biomimetic materials and neuromodulatory approaches delineate clear, actionable translational directions for PD centered on the laminin axis (Fig. 7 and Table 3). Thus, although laminin-related pathways may influence dopaminergic neuron maintenance, ECM remodeling, and cell-replacement strategies in PD, the field remains at an early and partly fragmented stage, and direct disease-defining mechanisms are not yet as well established as in vascular-BM pathology.

Fig. 7.

Roles and functions of laminin in PD. (Illustration created with Figdraw 2.0; authorization code: OOTUW44b4f)

Roles of laminin in ALS

ALS is a progressive, fatal neurodegenerative disorder involving both upper and lower motor neurons, typically presenting with progressive limb weakness, dysarthria/dysphagia, and respiratory failure; a subset of patients exhibit features along the frontotemporal degeneration spectrum. Most patients die within 2–5 years of symptom onset. Approximately 5–10% of cases are familial, with pathogenic or susceptibility genes including C9orf72, SOD1, TARDBP, and FUS; the remainder are largely sporadic and influenced by polygenic and environmental factors [334–337]. The global burden continues to rise: GBD 2019 estimated age-standardized prevalence for motor neuron diseases (including ALS) at ~3.37 per 100,000 and incidence at ~0.79 per 100,000 person-years, with growth driven by population aging and improved diagnosis [338]. No curative or broadly effective disease-modifying therapy exists. Pharmacologically, riluzole confers a small but statistically significant survival benefit, and edaravone shows signals for functional/survival benefit in selected populations and real-world studies, though overall evidence is limited and populations heterogeneous [339, 340]. Non-pharmacologic comprehensive care is likewise critical: randomized trials show that, in the absence of severe bulbar involvement, noninvasive ventilation significantly prolongs survival and improves quality of life; multidisciplinary management with timely nutritional/respiratory support and gastrostomy is also associated with improved survival [341, 342]. In translation, the FDA in 2023 granted accelerated approval of the antisense oligonucleotide tofersen (Qalsody) for SOD1-ALS, based on reductions in plasma neurofilament light (NfL) as a surrogate endpoint; by contrast, AMX0035 (Relyvrio) was voluntarily withdrawn in 2024 after the negative phase III PHOENIX trial, underscoring the challenges and uncertainties of ALS drug development. Clinical studies targeting genetic subtypes (nucleic-acid/gene therapies), proteinopathy (TDP-43), and fluid biomarkers (e.g., NfL) are ongoing [343–345].

Early dismantling of the NMJ is thought to be a pivotal driver of disease progression in ALS; as a core component of the synaptic BM, laminin—particularly the β2 and α4 chains—directly determines structural and functional homeostasis at the NMJ [86]. In mice, loss of laminin-β2 impairs formation/maintenance of presynaptic active zones, disrupts presynaptic differentiation, and reduces endplate potential frequency, weakening neuromuscular transmission [246]; deletion of laminin-α4 disrupts the precise apposition of active zones with postsynaptic folds and yields a “premature aging–like” NMJ phenotype, indicating a key role in adult NMJ maintenance [127, 247]. These findings align with synaptic BM remodeling/injury observed in ALS and support a cascade of BM–laminin disequilibrium → NMJ vulnerability → denervation. Clinically and in models, NMJ morphological abnormalities can emerge early in ALS [248], whereas extraocular muscles (EOM) are relatively “spared” in many patients [249]; their distinctive BM laminin isoform repertoire and signaling milieu may confer resistance to denervation, suggesting that modulating synaptic Laminins and their pathways could enhance NMJ resilience [250]. NMJ homeostasis also depends on the agrin–LRP4–MuSK pathway acting in concert with synaptic Laminins, further highlighting the therapeutic promise of the laminin–agrin–LRP4/MuSK axis in ALS [251, 252].

Multi-omics and histological studies reinforce this framework from several angles. Elevated laminin-1 expression has been observed in ALS skin [253]; in the spinal cord, γ1-laminin is selectively overexpressed in reactive astrocytes and strongly positive across multiple cervical/thoracic tracts [254]. In muscle, limb muscle BM in ALS may show reduced laminin α2/β2 and loss of α4, whereas EOM displays a distinct laminin profile; other reports note that “total laminin” may not change markedly, reflecting isoform-/stage-specific differences and sample heterogeneity [255, 256]. Along disease timelines in models, γ1-laminin progressively increases while the regeneration-inhibitory cue semaphorin-3A declines [257]. Targeting the blood–spinal cord barrier with cell therapy (transplantation of human bone-marrow endothelial progenitor cells) enhances “tight BM” laminin immunoreactivity and improves barrier structure, providing experimental support for ECM/BM-protective strategies [258]. In sum, from limiting inflammatory and blood–nerve/cord barrier disruption to bolstering NMJ resilience and promoting regeneration, a laminin-centered BM microenvironment and receptor–ligand network is emerging as a promising lens for understanding ALS progression and designing interventions (Fig. 8 and Table 3). Collectively, available data suggest that laminin may contribute to neuromuscular and axon–glia pathology in ALS, but the current evidence base remains limited and does not yet support a unified laminin-centered disease mechanism.

Fig. 8.

Roles and functions of laminin in ALS. (Illustration created with Figdraw 2.0; authorization code: UWRROeeae2)

Roles of laminin in MS

MS is an immune-mediated demyelinating and neurodegenerative disease of the CNS, manifesting clinically as relapsing–remitting, secondary progressive, or primary progressive phenotypes, with predominant sensory, motor, visual, and cognitive impairments. MRI-demonstrated demyelinating lesions and CSF oligoclonal bands aid diagnosis, and MS is a leading cause of neurological disability in young adults [346]. The global burden continues to rise: the MSIF Atlas of MS estimates that the number of people with MS increased from ~2.3 million in 2013 to ~2.8 million in 2020 and ~2.9 million in 2023, with marked regional disparities in access to diagnosis and care [347]. Over the past decade, disease-modifying therapies (DMTs) have expanded substantially, with the B-cell/anti-CD20 class supported by the strongest evidence: ocrelizumab reduced disease activity and risk of progression in RRMS (OPERA) and was the first to demonstrate efficacy in PPMS (ORATORIO); ofatumumab (ASCLEPIOS) and ublituximab (ULTIMATE) likewise lowered annualized relapse rates and MRI lesion activity in RRMS [348–350]. Therapeutic strategy is shifting from traditional “escalation” to early high-efficacy treatment; in highly active RRMS, AHSCT showed superior disease control in randomized trials [351]. Meanwhile, serum neurofilament light (sNfL) is accruing evidence for risk stratification and treatment monitoring, and etiologic studies indicate a strong association between EBV and MS pathogenesis [352, 353].

Pathologically, laminin is a hub ECM component of the BBB and cerebral microvascular BM. Its isoforms are heterogeneously distributed on postcapillary venules and “gate” leukocyte transendothelial migration—LM-511 strengthens endothelial junctions and suppresses extravasation, whereas LM-411–enriched segments more readily serve as leukocyte portals; thus, BBB laminin composition can directly drive inflammatory infiltration and lesion formation [28, 259, 260]. Correspondingly, active MS lesions frequently exhibit abnormal/lost laminin in vascular and astrocytic BMs with broader ECM remodeling, accompanied by shifts in integrin-receptor repertoires; peripheral lymphocytes from patients show enhanced laminin-degrading capacity correlated with disease activity, implicating protease-mediated BM breakdown in BBB destabilization [261–264].

In remyelination, laminin serves as both structural substrate and instructive cue: aligned along vessels and axons, it provides adhesive/migratory tracks and, via integrin–Fyn/FAK signaling, promotes oligodendrocyte progenitor cell (OPC) migration, survival, and differentiation. Multiple isoforms (LM-211/411/511) and their E8 fragments facilitate OPC responses and remyelination, directly linking ECM imbalance to repair failure [265–268]. Genetic and histologic data further reinforce this axis: rare/low-frequency variants implicate LAMA5 and LAMB1 in susceptibility [269]; LAMA2-related muscular dystrophy can present MS-like phenotypes [270]; loss of NG2 in OPCs/pericytes reduces BM molecules (including laminins and type IV/VI collagen) [271]; endothelial β1/VLA-6 downregulation or decoupling from laminin promotes leukocyte transit [262]; the MCAM–LM-411 axis facilitates TH17 entry into the CNS [272, 273]; “perivascular cuffs” are enriched for multiple laminin isoforms and other ECM components [274]; network/mechanobiology studies place LAMA1 at a nodal position within lesion networks [275], show that tissue stiffening correlates with inflammatory infiltration and increased laminin content [276], and reveal chronic-phase declines in dystrophin and laminin expression [277]. Additionally, high motility of Tregs on laminin substrates and upregulation of cortical Lama4/5 reflect coupling between immunity, BM composition, and tissue mechanics [278, 279].

Building on these mechanisms, interventions targeting the laminin–BM–immunity/repair axis show translational promise: natalizumab treatment reduces matrix metalloproteinases and increases TIMPs at peak and chronic phases, limiting BM laminin degradation and inflammatory infiltration [280]; berberine exerts neuroprotection by inhibiting gelatinase activity and reducing laminin degradation, providing pharmacologic support for ECM-protective strategies [281]. Overall, from controlling inflammatory ingress to promoting remyelination, remodeling of the BM microenvironment around laminin and tuning of integrin signaling are emerging as key levers for understanding MS progression and developing next-generation therapies (Fig. 9 and Table 3).

Fig. 9.

Roles and functions of laminin in MS. (Illustration created with Figdraw 2.0; authorization code: RIPWA5cc6c)

Roles of laminin in depression

Major depressive disorder (MDD) is a common psychiatric disorder characterized by persistent low mood, anhedonia, and cognitive and somatic symptoms, substantially impairing social and occupational functioning and increasing suicide risk [354–356]. Its global patient population is large, and its contribution to disability-adjusted life years (DALYs) remains high [357–359]. Evidence-based care emphasizes stepped and individualized treatment: psychotherapy (e.g., cognitive behavioral therapy, behavioral activation, interpersonal therapy) and antidepressants (e.g., SSRIs, SNRIs) constitute the foundation; for treatment-resistant or severe cases, repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive therapy (ECT) have robust efficacy, with multiple studies indicating larger acute effect sizes for ECT than for medications or rTMS [360–362]. Regarding novel mechanisms and therapies, ketamine/esketamine targeting the NMDA pathway offers rapid-onset options (with noninferiority signals versus ECT, though long-term outcomes remain to be established) [363]; the neurosteroid-targeting oral agent zuranolone has been approved for postpartum depression [364]; psychedelics (e.g., psilocybin) show dose-related short-term benefits in phase II trials of treatment-resistant depression but remain investigational [365]. Digital interventions (e.g., mobile behavioral activation) can reduce symptoms and improve quality of life in the short-to-medium term, though maintenance effects and real-world scalability require further high-quality evidence [366].

Biologically, laminin is a key protein of the cerebral microvascular BM and the perisynaptic ECM: it is essential for BBB homeostasis and provides “scaffold/instructive” cues for neurogenesis and synaptic plasticity. Reviews and mechanistic studies indicate that Laminin, by orchestrating interactions among endothelium, pericytes, and astrocytic endfeet, is a central regulator of BBB behavior and brain homeostasis; BBB dysfunction has been linked to mood disorders and cognitive impairment [28]. In depression-related models and human data, chronic stress downregulates Laminin in the hippocampus and frontal cortex, whereas antidepressants can partially reverse these changes, implicating ECM/Laminin in the plastic regulation along the stress–depression axis [282, 283]. Selective manipulation of LAMB1 in mice alters anxiety-/depression-like behaviors and pain sensitization in a region-specific manner, supporting a functional role for Laminin in affective regulation [284]. Antidepressants (e.g., fluoxetine) can induce hippocampal vascular remodeling with enhanced Laminin and CD31 sprouting, suggesting a “vascular–neurogenesis–ECM” coupling in therapeutic effects [285]. Upstream vulnerability factors include protease systems: tPA/plasmin can degrade Laminin, sensitizing hippocampal neurons to injury and indicating that stress-linked proteolysis may further undermine neural plasticity and survival by disrupting ECM–Laminin [286].

Further genetic and translational evidence also implicates the Laminin axis. EGFLAM (encoding EGF-like, fibronectin type III, and Laminin G domains) shows genome-wide significant association with cortical silent period in patients with depression [287]; the 67-kDa Laminin receptor is reduced in olfactory epithelial neural progenitors from patients with major depression/borderline personality disorder [288]. Adamts18 knockout mice exhibit reduced depression-like behavior and increased neuritogenesis, potentially via activation of the Laminin/PI3K/AKT/GSK-3β pathway [289]. LAMA5 has been proposed as a potential biomarker for concomitant myocardial hypertrophy and cardiac dysfunction in patients with depression [290]. Depressed patients show reduced Laminin levels in the parieto-occipital cortex [291], and an interaction between LAMA2 and illness duration influences right Heschl’s gyrus thickness [292]. Pharmacologically and in terms of plasticity, norepinephrine upregulates genes related to neuronal sprouting/differentiation (including Laminin) [293]; in a chronic-stress rat model, 3,6′-disinapoyl sucrose reverses anhedonia and downregulation of CAM-L1/Laminin/BDNF, suggesting that membrane protection/ECM remodeling may represent a promising antidepressant strategy [294] (Fig. 10 and Table 3). Taken together, the laminin axis is increasingly implicated in stress-related plasticity, vascular remodeling, and affective regulation; however, current evidence remains heterogeneous and should be interpreted as an emerging rather than definitive mechanistic field.

Fig. 10.

Roles and functions of laminin in depression. (Illustration created with Figdraw 2.0; authorization code: YOUPRe441c)

Roles of laminin in anxiety

Anxiety disorders constitute a group of common psychiatric conditions characterized by excessive anxiety/worry and avoidance, encompassing generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobias; they are frequently comorbid with depression and insomnia and substantially impair academic, occupational, and interpersonal functioning. The WHO notes a multifactorial biopsychosocial etiology [367]. Evidence-based care emphasizes stepped and individualized treatment, with first-line options including cognitive-behavioral therapy (CBT, with exposure) and antidepressants (SSRIs/SNRIs); benzodiazepines should not be used as first-line monotherapy and, when necessary, only for short, limited courses [368, 369]. Global burden studies indicate that anxiety disorders contribute prominently to years lived with disability; among U.S. adults, the 12-month prevalence is ~19.1% and lifetime risk is ~31.1% [370–372]. Recent research also supports internet-delivered CBT as effective in reducing anxiety symptoms and improving accessibility and scalability in both adults and adolescents; network meta-analyses of traditional and “third-wave” CBT confirm efficacy in the acute phase and over selected follow-up intervals [373–376].

Mechanistically across the anxiety spectrum, laminin—a key protein of the cerebral microvascular BM and the perisynaptic ECM—both preserves BBB integrity (limiting ingress of inflammatory mediators) and functions as an “instructive” scaffold regulating neuronal adhesion and plasticity. Animal and human evidence shows that selective downregulation of LAMB1 in the mouse anterior cingulate cortex (ACC) induces anxiety-/depression-like behaviors and alters synaptic/circuit activity, whereas restoring LAMB1 ameliorates the phenotype [284]. From a vascular perspective, abnormalities in the laminin/integrin axis weaken endothelial junctions and amplify neuroinflammation, promoting anxiety-related symptoms [28, 98]. At the synaptic level, laminin signaling and its bioactive fragments promote neurite growth and circuit remodeling, suggesting that ECM protection/reconstruction may offer a novel therapeutic pathway [101]. Overall, the coupling of laminin–BBB–synaptic plasticity not only contributes to the emergence and maintenance of anxiety but also provides actionable molecular entry points for ECM-targeted interventions.

Translational data further indicate that upstream signals can modulate anxiety-related phenotypes via the laminin axis: for example, retinoic acid (RA)/RA receptor-β transcriptionally regulates LAMB1 to maintain ECM homeostasis, reverse aberrant synaptic plasticity, and improve neuropathic pain and aversive affect, providing biological and pharmacologic rationale for targeting the RA–LAMB1–ECM/plasticity pathway in anxiety and its comorbidities (e.g., pain-related anxiety) [295] (Fig. 11 and Table 3). Overall, the relationship between laminin, BBB function, and anxiety-related circuit plasticity is biologically plausible but still supported by a relatively limited and mainly preclinical evidence base, and therefore should be considered an emerging area.

Fig. 11.

Roles and functions of laminin in anxiety. (Illustration created with Figdraw 2.0; authorization code: POTAR1d46d)

Roles of laminin in TBI

TBI is a heterogeneous syndrome of externally induced brain dysfunction/structural damage, ranging from mild concussion to severe diffuse/focal injury. Beyond acute mortality and disability, TBI can evolve into a “chronic disease” with long-term neuropsychiatric and cognitive consequences and is associated with increased late-life neurodegenerative risk; global annual incidence is estimated in the tens of millions [377]. In the United States, TBI-related deaths exceeded 69,000 in 2021, underscoring its public-health burden [378]. Clinical management centers on preventing secondary brain injury (correcting hypoxia/hypoperfusion, individualized ICP/CPP management, sedation and osmotherapy, etc.), guided by the 4th edition of the Brain Trauma Foundation (BTF) evidence-based guidelines [379]. For refractory intracranial hypertension, decompressive craniectomy lowered ICP in DECRA but did not improve functional outcomes, whereas RESCUEicp as a “salvage” procedure reduced mortality while increasing survival with severe disability/vegetative state, necessitating value-sensitive decision-making [380, 381]. Pharmacologically, CRASH-3 showed that tranexamic acid within 3 hours of injury reduced head injury–related death (particularly in mild–moderate TBI and with reactive pupils) [382], whereas large randomized trials of therapeutic hypothermia and progesterone did not demonstrate functional benefit [383, 384].

On diagnostics and systems of care, the blood biomarkers GFAP/UCH-L1 have FDA authorization to aid triage of adults with suspected mild TBI and guide head CT decisions [385, 386]; in 2023–2024, laboratory and point-of-care platforms gained expanded clearances, enabling streamlined emergency workflows and precision stratification [387]. In care pathways, the 2024/2025 American College of Surgeons “Best Practices” integrate biomarkers, imaging, and cross-continuum rehabilitation, emphasizing an acute–subacute–chronic strategy with early neurorehabilitation [388, 389]. Biologically, laminin, a key component of the cerebral microvascular BM, directly supports BBB stability: early post-injury upregulation of gelatinases (e.g., MMP-9) mediates proteolysis of BM constituents (including laminin), driving BBB rupture and secondary inflammation/edema; subsequently, reactive remodeling ensues, with peri-lesional re-expression/upregulation of laminin, reflecting a temporal pattern of acute loss → subacute remodeling [21, 296–298]. In controlled cortical impact models, laminin and fibronectin rise markedly within the peri-contusional “penumbra” by day 3 and persist to day 14, implicating roles in barrier repair and regulation of gliosis [299]. Systematic reviews likewise indicate that laminin changes mirror BBB structural integrity and associate with permeability deficits in TBI/intracerebral hemorrhage [30]. Concomitantly, TBI induces NVU architectural changes (e.g., BM thinning, rapid pericyte responses/migration), reinforcing the centrality of the BM–laminin axis in microenvironmental homeostasis [300]. Extracerebrally, contralateral limb muscle shows upregulation of laminin and type IV collagen [301], and post-traumatic cerebrovascular dystrophin loss couples with altered vascular laminin immunoreactivity [302].

For regeneration and repair, ECM/laminin-guided biomaterials and cell therapies show feasibility: laminin-based scaffolds enhance neural stem cell survival and integration in injured brain [303]; self-assembling peptide hydrogels containing IKVAV (a laminin-derived motif) or functionalized RADA16 reduce acute apoptosis/inflammation, promote neuritogenesis, and improve outcomes in TBI/ICH models [31, 304, 305]. Additional engineered platforms include IKVAV bioactive peptides tailored for TBI [306], laminin-coated electronic scaffolds with vascular topology [307], multi-component anti-inflammatory hydrogels incorporating Fmoc-DIKVAV and fucoidan to attenuate glial scarring [308], implantation of human meningioma stem cells into IKVAV nanoscaffolds [309], and hyaluronan–laminin hydrogels that enhance chemotaxis to SDF-1α gradients and graft integration [310]. Systemic/targeted interventions also yield ECM/BBB-related gains: valproate plus fresh frozen plasma improved BBB integrity and upregulated laminin in TBI with hemorrhagic shock [311]; exosome therapy in large animals enhanced neuroprotection and BBB, increasing levels of laminin, claudins, and ZO-1 [312]; the PARP inhibitor PJ34 reduced MMP-9, increased claudins, laminin, collagen IV, and integrin β1, and lessened contusion volume and neurological deficits [313]. Overall, TBI research and care are converging toward precision stratification (imaging + biomarkers) × longitudinal rehabilitation × ECM/laminin-targeted repair (Fig. 12 and Table 3).

Fig. 12.

Roles and functions of laminin in TBI. (Illustration created with Figdraw 2.0; authorization code: UTART2ddd0)

From mechanisms to the clinic: opportunities, challenges, and safety considerations

Current translational opportunities of laminin-targeted strategies

From a mechanistic-to-clinical perspective, laminins play dual roles in the nervous system as both structural scaffolds and signaling hubs. At the BBB BM, LM-411 serves as the vascular ligand for MCAM (CD146), promoting transendothelial migration of pathogenic Th17 cells; animal studies show that blocking the MCAM–LM-411 axis reduces CNS infiltration and mitigates inflammation, providing druggable evidence for a “second route” of immune entry into the parenchyma, while also highlighting the need—during clinical translation—to balance effects on physiological immune surveillance and barrier homeostasis [272, 390]. At synapses, LM-β2 is a key organizer of the NMJ active zone, clustering voltage-gated calcium channels and determining presynaptic differentiation and miniature endplate potential frequency; the α4 and β2 chains respectively influence active-zone positioning and density, revealing Laminin’s fine-grained division of labor in synaptic transmission efficiency and circuit stability [246, 391]. These foundations motivate “barrier regulation + synaptic repair” as mechanistic targets; in parallel, Laminin can directly modulate protein aggregation—in vitro it inhibits Aβ40/42 fibrillization—suggesting disease-modifying potential in the amyloid pathology of AD [209, 392].

Three principal clinical/engineering opportunities follow. (i) Clinical-grade stem/progenitor manufacturing: recombinant human LM-511/521 and their E8 fragments (LN-511/521-E8) markedly enhance hPSC adhesion, survival, and single-cell passaging stability under xeno-free, chemically defined conditions, and have become mainstay GMP substrates; mechanistically, they promote survival via α6β1–Fyn–RhoA/ROCK signaling [115, 229, 393–395]. (ii) Biomaterials and regenerative medicine: self-assembling peptide nanofibers/hydrogels bearing the Laminin-derived IKVAV epitope suppress glial scarring, promote neuritogenesis, and enhance neural stem-cell integration, with functional improvements reported in brain/spinal cord injury models and scalable combinations with RADA16 platforms [31, 232, 396]. (iii) Biomarkers and stratification: imaging or fluid biomarkers targeting the MCAM–LM-411 axis may help characterize the coupled immune–barrier–circuit state, guiding timing and patient selection for precision interventions (e.g., complementing or substituting existing anti-adhesion strategies) [390]. However, such biomarker concepts remain preliminary. Current evidence is uneven across preclinical and human settings, and specificity may be limited by confounders such as systemic vascular injury, peripheral BM remodeling, muscle disease, and other non-CNS sources of laminin-related signals. Accordingly, these candidates should presently be interpreted as adjunctive and hypothesis-generating rather than disease-defining biomarkers.

Challenges and safety considerations are equally salient. First, Laminin isoforms and conformations are highly context-dependent: early inflammatory activation of MCAM–LM-411 amplifies immune ingress, yet excessive blockade may impair necessary immune patrol; risk mitigation in trials will require careful control of exposure, timing, and site of delivery [272, 390]. Second, mechanobiology and adhesion signaling display dose–response and lineage-specific effects: while the α6β1–Fyn–ROCK pro-survival effect of LN-511/521 benefits hiPSC manufacturing consistency, it could alter adhesion/migration thresholds in neuro-oncologic or reactive glial microenvironments, warranting systematic tumor-safety evaluation when extending indications or selecting implantation sites [395]. Third, long-term material biocompatibility and degradation products require validation in large animals and early-phase trials (e.g., chronic responses to IKVAV-functionalized hydrogels in brain tissue; stability and electrochemical safety of conductive/visualizable scaffolds) [232]. Overall, a feasible path forward is to center on isoform-specific Laminin combinations, integrating xeno-free cell manufacturing, multimodal immune–barrier–plasticity metrics, and locally controlled-release biomimetic materials, while advancing dose-finding, companion diagnostics, and longitudinal safety within evidence-based frameworks—thereby closing the loop from mechanistic validation to clinically effective and affordable translation.

Translational feasibility and limitations of laminin-targeted therapies

Although laminin is increasingly discussed as an actionable therapeutic target, the current evidence supports a more cautious interpretation: laminin is better viewed as a context-dependent and partially tractable ECM axis rather than a uniformly druggable target. Its translational feasibility varies substantially according to the therapeutic format, the laminin isoform involved, the disease stage, and the anatomical site of intervention.

A central issue is isoform specificity. Unlike soluble cytokines or single-enzyme targets, laminins are large heterotrimeric basement-membrane proteins with strong spatial and temporal heterogeneity. In the nervous system, LM-411, LM-511/521, LM-211, and synapse-associated laminins play nonredundant roles in vascular integrity, immune-cell trafficking, myelination, and synaptic organization. This implies that broad enhancement or blockade of “laminin signaling” is unlikely to be uniformly beneficial. For example, laminin species that support BBB stability in one context may also facilitate cell adhesion, migration, or matrix remodeling in another. Therefore, the most plausible translational strategies are not pan-laminin interventions, but rather isoform-selective or receptor-axis-selective approaches, particularly those directed at disease-relevant laminin–integrin or laminin–MCAM interactions within defined neurovascular compartments.

A second challenge concerns on-target toxicity and physiological dependence. Laminins are indispensable for basement-membrane assembly, developmental patterning, vascular maturation, synaptic organization, and tissue homeostasis. This raises an inherent translational tension: the same molecules that are mechanistically attractive in disease are also essential for normal structure and function. Excessive interference may therefore destabilize BBB architecture, perturb synaptic alignment, impair regenerative cell–matrix interactions, or disrupt long-term tissue maintenance. This concern is especially relevant for α5-containing laminins and other broadly distributed isoforms, whose functions extend beyond diseased regions. Accordingly, systemic and sustained manipulation may carry a narrower therapeutic window than local or time-restricted intervention.

A third limitation is druggability and delivery. Full-length laminins are difficult therapeutic molecules because of their very large size, structural complexity, manufacturing cost, and poor pharmacokinetic tractability. Intravenous administration faces the additional obstacle of the BBB, which severely limits CNS exposure and complicates dose control. For this reason, the approaches currently closest to practical translation are not native full-length laminin replacement, but rather laminin-derived peptides, recombinant functional fragments, and biomaterial-based presentation systems. Short bioactive motifs such as IKVAV and YIGSR, as well as recombinant E8 fragments, are more manufacturable and have already shown utility in stem-cell culture, neural differentiation, and regenerative biomaterials. However, these simplified formats only capture part of laminin biology and may not reproduce the full structural, mechanical, and multireceptor functions of intact basement membranes.

From a translational standpoint, biomaterials and local matrix engineering currently appear more clinically approachable than systemic molecular targeting. Hydrogels, self-assembling peptides, scaffold coatings, and laminin-functionalized regenerative matrices allow spatially restricted presentation and may reduce systemic toxicity. These approaches are particularly attractive in settings such as neural repair, cell transplantation, or peri-lesional tissue reconstruction, where local ECM reprogramming is a realistic therapeutic objective. By contrast, systemic blockade of laminin-associated pathways for inflammatory or vascular indications may be more difficult to control because benefit depends strongly on timing, barrier status, and cell-type specificity.

Gene-therapy-based approaches are conceptually promising but currently further from routine neurological application. Inherited neuromuscular disorders have provided proof-of-principle that linker proteins, mini-agrin-related strategies, or other ECM-engineering concepts can partially compensate for laminin-network defects. However, extension of this logic to acquired CNS diseases remains challenging because efficient brain-wide delivery, cell-type-selective expression, long-term safety, and control of matrix stoichiometry are unresolved. In addition, excessive or ectopic expression could theoretically disturb basement-membrane homeostasis or produce maladaptive remodeling.

Importantly, laminin should also be discussed in relation to other ECM targets, because it is unlikely to act in isolation. Compared with type IV collagen, which primarily provides tensile scaffold and vascular mechanical support, laminin is more directly involved in receptor-mediated signaling, polarity instruction, and cell-matrix communication. Compared with perlecan, which is particularly prominent in growth-factor sequestration and perivascular signaling regulation, laminin has a stronger role in adhesive organization and basement-membrane assembly. Compared with agrin, which is especially specialized in synaptic and neuromuscular junction organization, laminin occupies a broader structural position across vascular, glial, and synaptic basement membranes. This comparison suggests that laminin may be a more versatile intervention node, but it also means that laminin-directed therapy carries broader pleiotropic risk than targeting more functionally restricted ECM components. In practice, combinatorial ECM strategies—or approaches aimed at restoring matrix balance rather than altering one component in isolation—may prove more realistic than single-target paradigms.

Another point that warrants explicit emphasis is that translation attempts remain largely preclinical and, in many cases, still exploratory rather than definitive. Much of the supportive evidence comes from in vitro systems, rodent injury models, stem-cell manufacturing studies, or biomaterial proof-of-concept work. These studies are highly valuable mechanistically, but they do not yet establish clear dose–response relationships, optimal treatment windows, long-term safety, or superiority over alternative ECM-directed strategies. Thus, at the current stage, it would be more accurate to describe laminin-targeted therapy as a promising but still early translational field, rather than a validated therapeutic direction.

Taken together, the approaches currently nearest to clinical application appear to follow a practical hierarchy: (i) laminin-derived peptides and recombinant fragments for ex vivo cell manufacturing or local regenerative use; (ii) laminin-functionalized biomaterials and scaffold-based delivery systems; and (iii) more selective receptor-axis modulation in narrowly defined disease settings. In contrast, systemic full-length laminin administration and broad in vivo gene-augmentation strategies remain less mature because of delivery, specificity, and safety barriers. Future progress will depend on matching the appropriate laminin format to the appropriate disease context, while integrating isoform specificity, BBB delivery constraints, and the risk of disrupting physiological basement-membrane homeostasis.

Human-relevant models, spatial benchmarking, and clinically informative trial design warrant higher priority in the next phase of translation. Although much of the current evidence for laminin-targeted strategies derives from animal models and reductionist 2D systems, future studies should increasingly incorporate human-centric platforms, including hiPSC-derived neurovascular organoids, vascularized or perfused BBB-on-chip systems, and ex vivo human brain slices. These models can better preserve human-specific cell composition, extracellular-matrix architecture, and neurovascular interactions, and may therefore provide more predictive readouts for laminin isoform biology, BBB remodeling, and treatment response. In parallel, the growing use of high-resolution spatial transcriptomics in neurovascular research calls for unified evaluation frameworks across platforms and centers. Rather than relying solely on descriptive spatial maps, future laminin studies should incorporate standardized metrics such as reproducibility, sensitivity, dynamic range, signal-to-noise ratio, false discovery rate, segmentation quality, annotation accuracy, and concordance with orthogonal single-cell datasets. Such standardization will be particularly important for resolving laminin-rich vascular and perivascular niches, where biological interpretation is highly dependent on spatial precision. On the therapeutic side, targeted-delivery platforms deserve more detailed consideration. Peptide-functionalized nanocarriers—including lipid nanoparticles, liposomes, polymeric nanoparticles, and biomimetic systems—offer a potentially tractable route to improve BBB transcytosis, enhance regional brain accumulation, and reduce systemic off-target exposure for laminin-directed cargoes or matrix-modulating agents. However, their translational performance will depend on receptor selectivity, protein-corona effects, release kinetics, endosomal escape, and safety under repeated dosing. Finally, future early-phase clinical studies should move beyond biomarker description alone and adopt mechanism-informed designs that pair matrix- or barrier-related biomarkers with functional endpoints. Biomarker-enriched enrollment, longitudinal monitoring of BBB/ECM remodeling, and composite outcome frameworks linking exposure, target engagement, and clinical function may improve both interpretability and translational value.

Remaining evidence gaps and methodological limitations

Despite rapid progress, several broader limitations still constrain the field. An additional challenge is the uneven maturity of evidence across disease categories: mechanistic and translational support is comparatively stronger for stroke, BBB-related pathology, and neurodevelopmental contexts, whereas for AD, PD, ALS, depression, and anxiety, the available evidence remains more heterogeneous and is often associative, preclinical, or fragmentary. First, much of the current evidence remains preclinical and is derived from 2D cell systems, acute-injury models, or short-term intervention studies, which only partially recapitulate the chronic, heterogeneous, and multicellular nature of neurological disorders.

Second, methodological resolution remains insufficient for defining when, where, and how laminin alterations become pathogenic or reparative. Spatiotemporal measurements of ECM proteolysis, glycosylation, sulfation, and receptor engagement are still limited, and emerging approaches such as spatial transcriptomics, mass-spectrometry imaging, and single-cell multi-omics have not yet been integrated into unified evaluation frameworks. This makes it difficult to establish robust chain–receptor–function relationships across models and disease contexts.

Third, major standardization gaps remain at the translational interface. GMP-grade production, lot-to-lot consistency, long-term stability, and quality standards for engineered matrices or degradable scaffolds are still evolving. At the clinical level, biomarker-guided patient stratification is underdeveloped, and trial designs rarely link matrix-related biomarkers to disease-relevant functional endpoints, dose–exposure–response relationships, or long-term benefit–risk assessment. Existing registered studies are often small, open-label, or short in follow-up, limiting definitive conclusions.

Overall, future progress will depend on more predictive human-relevant models, standardized multimodal evaluation systems, and closer integration of mechanistic biomarkers with longitudinal functional outcomes. These advances will be essential for moving laminin research from mechanistic promise toward reproducible and clinically informative translation.

Conclusions and perspectives

Overall, this review connects the Laminin family from a “BM structural hub” to an “intervention-ready node in neurological disease.” By engaging a parallel receptor network composed of integrins, α-dystroglycan, and HSPG/syndecan, Laminin couples mechanical support to signal transduction and occupies a central position in the development, homeostasis, and repair of the BBB/NVU, synaptic architecture, and the myelin–Nodes of Ranvier microstructure. On the translational front, materials/devices and microenvironments based on functional peptides and engineered fragments have taken shape: IKVAV and related bioactive motifs drive neuroregeneration; the α6β1–Laminin-511 complex (E8 fragment) provides a high-affinity, xeno-free standard matrix for human cells; and “linker” proteins such as αLNNd/mini-agrin demonstrate the feasibility of a “repair the mesh with the mesh” gene-therapy paradigm.

Looking forward, three priorities may accelerate clinical translation of laminin research. First, human-relevant neurovascular models—such as vascularized organoids, perfused microphysiological BBB systems, and ex vivo brain slices—should be integrated earlier into preclinical pipelines to bridge the current translational gap. Second, spatially resolved laminin research should move toward unified benchmarking standards so that cross-platform and cross-cohort comparisons become biologically and clinically interpretable. Third, clinical development should adopt biomarker-linked functional trial designs, in which laminin-related or BBB-related readouts are paired with disease-relevant neurological endpoints rather than being treated as isolated exploratory measures. Together, these advances would help shift laminin research from descriptive association toward mechanism-anchored and clinically actionable translation.

Electronic supplementary material

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Abbreviations

IS

Ischemic stroke

HS

Hemorrhagic stroke

AD

Alzheimer’s disease

PD

Parkinson’s disease

MS

Multiple sclerosis

GBD

Global Burden of Disease

NVU

Neurovascular unit

BBB

Blood–brain barrier

CNS

Central nervous system

HSPG

Heparan sulfate proteoglycan

MMP

Matrix metalloproteinase

VCI

Vascular cognitive impairment

ALS

Amyotrophic lateral sclerosis

TBI

Traumatic brain injury

ECM

Extracellular matrix

BM

Basement membrane

EHS

Engelbreth–Holm–Swarm

α-DG

α-Dystroglycan

LG

Laminin G

DGC

Dystrophin–glycoprotein complex

NMJ

Neuromuscular junction

HBD

Heparin-binding domains

ILM

Inner limiting membrane

VGCC

Voltage-gated calcium channel

LTP

Long-term plasticity

BMEC

Brain microvascular endothelial cells

ICH

Intracerebral hemorrhage

aSAH

Aneurysmal subarachnoid hemorrhage

Aβ

β-Amyloid

IPAD

Intramural periarterial drainage

LRP/LR

Laminin receptor

DBS

Deep brain stimulation

mDA

Midbrain dopaminergic

NfL

Neurofilament light

EOM

Extraocular muscles

DMT

Disease-modifying therapies

OPC

Oligodendrocyte progenitor cell

MDD

Major depressive disorder

DALY

Disability-adjusted life years

rTMS

Repetitive transcranial magnetic stimulation

ECT

Electroconvulsive therapy

CBT

Cognitive-behavioral therapy

ACC

Anterior cingulate cortex

RA

Retinoic acid

BTF

Brain Trauma Foundation.

Author contributions

All authors have materially participated in the research and article preparation. The roles for all authors are follows: Xingfang Zhang: Data curation, Formal analysis, Writing—original draft. Xiaohui Li: Formal analysis, Writing—original draft. Liang Gao: Formal analysis, Writing—original draft. Yajun Qiao: Formal analysis, Investigation. Bowen Lv: Formal analysis, Investigation. Qiudong Zhang: Formal analysis. Mengye Zhang: Investigation. Jiping Yu: Investigation. Hua Li: Investigation. Hongtao Bi: Conceptualization, Formal analysis, Writing—review & editing. Yi Ding: Conceptualization, Methodology, Writing—review & editing. All authors have approved the final version of the manuscript.

Funding

This work was financially supported by the National Natural Science Foundation of China (82274313), Key Research and Development Program of Shaanxi (2023-ZDLSF-57) and Special Funds for Central Government to Guide Local Scientific and Technological Development (2025ZY010).

Data availability

Not applicable.

Declarations

Ethics approval

Not applicable.

Conflict of interest

The authors declare no conflicts of interest.