Crucial role of microglia-mediated myelin sheath damage in vascular dementia: Antecedents and consequences

Abstract

Chronic cerebral hypoperfusion can lead to neuronal necrosis, trigger inflammatory responses, promote white matter damage, and ultimately result in cognitive impairment. Consequently, chronic cerebral hypoperfusion is an important factor influencing the onset and progression of vascular dementia. The myelin sheath is a critical component of white matter, and damage and repair of the white matter are closely linked to myelin sheath integrity. This article reviews the role of microglia in vascular dementia, focusing on their effects on myelin sheaths and the potential therapeutic implications. The findings suggest that ischemia and hypoxia cause disruption of the blood–brain barrier and activate microglia, which may worsen blood–brain barrier damage through the release of matrix-degrading enzymes. Microglia-mediated metabolic reprogramming is recognized as an important driver of inflammation. Damage to the blood–brain barrier and subsequent inflammation can lead to myelin injury and accelerate the progression of vascular dementia. Early activation of microglia is a protective response that contributes to the maintenance of blood–brain barrier integrity through sensing, debris-clearing, and defensive mechanisms. However, prolonged activation can trigger a shift in microglia toward the pro-inflammatory M1 phenotype, resulting in myelin damage and cognitive impairment. Triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells 1 have been identified as potential biomarkers for vascular dementia, as both are closely linked to cognitive decline. Although effective clinical treatments for myelin damage in the central nervous system are currently lacking, researchers are actively working to develop targeted therapies. Several drugs, including nimodipine, dopaminergic agents, simvastatin, biotin, and quetiapine, have been evaluated for clinical use in treating microglial and myelin damage. Future research will face challenges in developing targeted therapeutic strategies for vascular dementia, requiring further investigation into the timing, duration, and specific mechanisms of microglial activation, as well as the exploration of new drug combinations and additional therapeutic targets.

Introduction

Vascular dementia (VaD) refers to a severe cognitive dysfunction syndrome that affects memory, cognition, and behavior. VaD is caused by cerebral vascular diseases such as ischemic stroke, hemorrhagic stroke, and cerebral hypoperfusion. It is the most common type of dementia after Alzheimer’s disease (AD). The incidence rate of VaD increases with age, with the risk of VaD doubling every 5.3 years of age. A 2020 epidemiological survey showed that the overall rate of VaD among Chinese individuals aged 60 years and above was 16%. With the accelerated aging of the Chinese population (Jia et al., 2020), the proportion of individuals aged 60 years and above in China’s total population will reach 30% by 2035. This disease imposes a heavy burden on families and society, and has become a major health issue faced by the medical community. Therefore, effective means and drugs for preventing and treating VaD are essential.

The pathogenesis of VaD is unclear, and chronic cerebral hypoperfusion (CCH) caused by cerebrovascular risk factors is an important factor in the occurrence and progression of VaD (Iadecola et al., 2019). Reduced blood flow in the brain can affect the supply of oxygen and nutrients to nerve cells, leading to damage or even death of nerve cells, and can trigger inflammatory reactions, resulting in damage to white matter and cognitive impairment (Yang et al., 2022b). The activation of microglia (MG) may serve as a pivotal element in this process, since activated MG are capable of releasing a substantial array of pro-inflammatory cytokines, precipitating considerable oxidative stress (Kwon and Koh, 2020). In addition to engendering neuronal degeneration, the release of these agents also causes axonal damage and induces demyelination (Zhang et al., 2024).

The myelin sheath, meticulously constructed by mature oligodendrocytes (OLs), envelops the axonal projections of neurons, forming an insulating layer that accelerates neural signal transmission and facilitates the swift conveyance of nerve impulses between neurons. This phenomenon is essential for seamless operation of motor, sensory, and cognitive functions. Moreover, the myelin sheath plays a crucial role in guiding axonal regeneration following injury and is integral to the central nervous system (CNS). Consequently, the formation of the myelin sheath is regarded as the final authentic “invention” in the cellular architecture of the nervous system within vertebrate evolution (Nave, 2010). However, activation of MG can induce oxidative stress and inflammatory responses, ultimately leading to myelin degradation and lesions within white matter. As white matter contains a vast network of myelinated nerve fibers and constitutes 60% of the brain’s volume (Krafft et al., 2012), such damage further disrupts the rapid propagation of nerve impulses. These changes culminate in cognitive impairments, as high transmission velocity is fundamental to effective motor, sensory, and cognitive performance (Li et al., 2019).

MG are resident immune cells in the CNS, constituting approximately 10% to 15% of the total CNS cell population. In healthy brain tissue, MG exist in a highly branched, resting state, known as resting MG. Despite their quiescent appearance, these cells maintain direct contact with neuronal synapses, continuously monitoring their functional status and ensuring dynamic and efficient surveillance of the brain’s microenvironment (Cserép et al., 2020). When the brain encounters inflammation, infection, or other pathological conditions, MG swiftly recognize damage or infectious agents in their surroundings, namely damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), to maintain the dynamic balance of the brain. The recognition of DAMPs or PAMPs by MG triggers rapid activation of MG, which engage in phagocytosis to clear cellular debris and dead neurons (Simpson and Oliver, 2020). Initially, the activated MG primarily regulate the innate immunity of the CNS and initiate appropriate inflammatory responses, which are referred to as neuroinflammation and are the fundamental reactions to protect the CNS. However, uncontrolled or prolonged neuroinflammation can lead to a cascade of harmful reactions. In various ischemic diseases, MG have been identified as an important source of pro-inflammatory molecules, which can damage other CNS components such as neurons and OLs, resulting in neurotoxicity and thereby promoting the occurrence and development of the disease (Planas, 2024). Interestingly, recent studies have revealed a beneficial role of MG in myelin clearance and regeneration, in contrast to their traditionally perceived harmful effects. During the process of demyelination, MG actively participate in the phagocytosis of myelin debris and apoptotic cells, which express cytokines and chemokines, facilitating the activation of endogenous oligodendrocyte progenitor cells (OPCs) and their recruitment to lesion sites (Romero-Ramírez et al., 2024). As the myelin begins to reform, MG undergo a phenotypic switch from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype (Yang et al., 2023). Thus, MG play a dual role in regulating pathological and physiological inflammatory responses. This complexity increases the challenge for researchers studying disease development mediated by MG and remains a focal point and challenge in current neuroscience research.

The lack of effective therapeutic agents for myelin injury in the CNS represents a major unmet medical need. Notably, a multitude of drugs that showed successful pro-myelinating potential in OPC cultures failed in animal models or clinical trials, indicating major obstacles that hinder simple remyelination therapies. However, a growing body of research has shown that certain well-established medications, although not originally designed for myelin damage, have unexpected efficacy in preventing myelin damage and promoting myelin repair. For instance, the antipsychotic drug quetiapine has been shown to promote the differentiation of neural precursor cells into OLs and enhance myelin basic protein synthesis and myelin formation by activating extracellular signal related kinase 1 and 2 (ERK1/2) (Ren et al., 2013). The antihypertensive drug nimodipine can selectively induce apoptosis in IBA1⁺ cells and improve the survival of mature OLs, leading to an increase in the number of myelinated axons and causing functional recovery (Schampel et al., 2017). Domperidone can regulate OL precursor proliferation and repair myelin damage by inducing prolactin release (Gregg et al., 2007). Simvastatin, which is used to treat hypercholesterolemia, can promote the survival and differentiation of OL progenitors, thereby fostering myelin regeneration (Paintlia et al., 2005). Biotin may promote myelin regeneration by enhancing myelin phospholipid formation in OLs and potentially by boosting brain energy production to protect demyelinated axons from degradation (Sedel et al., 2016). In addition to offering a novel direction for treating myelin-related disorders, these findings also provide insights for the development of new medications. Overall, the development of drugs to treat CNS myelin injury is a daunting but extremely important field. A more profound understanding of the mechanisms and pharmacokinetic properties of myelin injury can better inform clinical trials. Furthermore, active exploration of drug combinations and new drug discovery is essential to enhance the treatment of diseases associated with myelin injury.

Search Strategy

To conduct this review, the literature was searched using a combination of the following terms: “microglia” AND “vascular dementia,” “chronic cerebral hypoperfusion” AND “vascular dementia,” “white matter” AND “microglia” OR “vascular dementia,” “myelin sheath” AND “microglia” OR “vascular dementia,” “brain ischemia” AND “microglia” “immune-inflammatory” AND “microglia” AND “vascular dementia,” and “clinical trials” AND “therapeutic drugs” AND “myelin damage.” The PubMed database was used to identify relevant articles published between January 2000 and November 2024. The selected articles covered the protective effects of early activated MG on VaD, myelin damage mediated by sustained activated MG, potential biomarkers of VaD, and drugs that can treat myelin damage.

Figure 1 presents an outline of the major events in this process. MG become active only 30 minutes after a transient ischemic attack (Schilling et al., 2005) and accumulate at the damaged blood–brain barrier (BBB) (Jolivel et al., 2015). Thus, MG may play an important role in cerebral ischemic diseases. Subsequent studies have shown that MG play three protective roles in VaD: perception, housekeeping, and defense roles (Hickman et al., 2018). In terms of specific mechanisms, MG have a major effect on myelin damage. M1-type MG can lead to overexpression of cyclooxygenase-2 (COX-2) in demyelinating lesions (Carlson et al., 2006). The activation of triggering receptor expressed on myeloid cells 2 (TREM2) on MG promotes the formation of mature OLs, thereby promoting myelin regeneration and maintaining axonal integrity (McQuade et al., 2020). DAP12 can regulate the ability of MG to engulf apoptotic cells and myelin debris, promoting myelin repair (Zhou et al., 2023). Gene knockout experiments have demonstrated that TREM2 plays a crucial role in myelin regeneration (McCray et al., 2024). At the level of drug research, biotin has been suggested to promote myelin regeneration by enhancing the formation of myelin phospholipids in OL (Sedel et al., 2016). Nimodipine can selectively induce apoptosis in IBA1⁺ cells, improve the survival rate of mature OLs, and lead to an increase in myelinated axons and functional recovery (Schampel et al., 2017). Despite the absence of specific drugs for VaD, current drug research has also highlighted the direction for the development of new drugs in the future.

Figure 1.

The timeline displays the association between MG, VaD, and the myelin sheath, along with drugs that have therapeutic effects on myelin sheath injury.

BBB: Blood–brain barrier; COX-2: cyclooxygenase-2; DAP12: DNAX-activating protein of 12 kDa; MBP: myelin basic protein; MG: microglia; OL: oligodendrocytes; TREM2: triggering receptor expressed on myeloid cells 2; WAM: white matter associated microglia.

Early Activation of Microglia in Vascular Dementia

As the sentinel immune cells of the brain, MG serve as the first responders to infection or tissue damage, initiating an inflammatory response—a fundamental immune reaction aimed at shielding the body from endogenous and exogenous insults. After ischemia, MG undergo rapid activation, showing changes in shape and function distinct from their resting state. These changes result in observable phenotypic shifts (Maida et al., 2020), giving rise to a diverse array of inflammatory mediators with harmful and protective properties (Candelario-Jalil et al., 2022). These mediators can either exacerbate or repair damage, depending on the spatiotemporal progression of structural harm (Anttila et al., 2017). Currently, ample evidence suggests that the activation and proliferation of MG occur in the early stages of numerous ischemic diseases. Schilling et al. (2005) observed that MG became active merely 30 minutes after transient ischemic attacks and show a subsequent numerical increase within a few days. In the VaD model, activation of MG was noted on the first day after bilateral carotid artery ligation in rats, albeit without statistical significance at this point (Sun et al., 2021). However, activation peaked on the third post-surgical day, with approximately 86% of the MG in an activated state. Although the number of MG declined between the 7^th and 28^th post-surgical days, 58% remained activated on the 28^th day (Sun et al., 2021). Activated MG engage in a dual role: on one hand, they phagocytose cellular debris and clear damaged cells, while on the other hand, they express immunoglobulin Fc receptors (such as CD16/CD32) and release pro-inflammatory cytokines (e.g., tumor necrosis factor-α [TNF-α], interleukin [IL]-1β, IL-6), metabolic enzymes (such as inducible nitric oxide synthase [iNOS]), nitric oxide (NO), and metabolic byproducts (such as reactive oxygen species [ROS]) to drive inflammatory processes and expedite neuronal demise in response to pathological changes or various stimuli, including lipopolysaccharide (LPS) and interferon (IFN)-γ (Yang et al., 2022b). Although current research has been predominantly focused on the phenotypic alterations and activation triggers of MG, endeavors aimed at reinstating their original state following injury remain challenging. Consequently, directing attention to the early triggers of MG activation may prove beneficial in averting the onset of injury.

Destruction of the blood–brain barrier

The disruption of the BBB appears to precede MG activation. This is exemplified by a brief, yet severe, BBB disruption in the corpus callosum (CC) after CCH. The BBB sustained severe damage on the first post-surgical day, with the damage peaking on the third day (Sun et al., 2021). Similarly, BBB disruption has been observed in the CA1 area of the rat hippocampus 1 day after CCH, although statistically significant differences emerged 3 days post-surgery, reaching a climax on the 7^th day (Qu et al., 2020). Notably, rats exhibited considerable cognitive impairment 14 days after surgery (Zhang et al., 2020b). Thus, BBB destruction following CCH may induce activation of MG, potentially culminating in neuronal damage, white matter degeneration, and, ultimately, cognitive impairment. The BBB consists of three protective barriers: cerebral capillary endothelial cells (ECs) and their tight junctions, the basement membrane, and the terminals of astrocytes (AS). Two studies have demonstrated that the BBB is severely damaged in neurodegenerative diseases (Andjelkovic et al., 2023; Hu et al., 2023). A comprehensive meta-analysis revealed that BBB permeability increases with age in healthy individuals and is further exacerbated in patients with VaD (Farrall and Wardlaw, 2009). Various factors cause disruption of the BBB, including genetic predisposition (apolipoprotein E, superoxide dismutase-1, aquaporin-4), oxidative stress (enzymes, antioxidants), neuroinflammation, gut microbiota, traumatic brain injury, ischemia, and hypoxia (Aragón-González et al., 2022). However, the existing research has largely overlooked the origins of early BBB impairment in VaD, instead focusing primarily on the secondary BBB damage that ensues following inflammation or oxidative stress outbreaks.

Within minutes of acute cerebral ischemia, adenosine triphosphate (ATP) levels sharply decrease, intracellular calcium levels increase, and glutamate excitotoxicity and acidosis occur. These changes are followed by increased expression of early response genes (such as c-jun, c-fos) and proteases within hours (Wang et al., 2022). Within 2 hours of oxygen-glucose deprivation in microvascular ECs, matrix metalloproteinase (MMP)-2 initiates the degradation of occludin, and caveolin-1 orchestrates the redistribution of claudin-5, resulting in augmented passage of fluorescein isothiocyanate-conjugated 70-kDa dextran across the endothelial monolayer and signifying a disruption of its barrier function. This event was similarly observed 2 hours after middle cerebral artery occlusion in rats (Liu et al., 2012). Subsequently, within 4 hours of acute ischemia, upregulated vascular endothelial growth factor expression triggered an angiogenic response, leading to local collapse of ECs and causing serum components (such as albumin or fibrinogen) to permeate from the bloodstream into the brain parenchyma. These components recruit nearby MG and foster their breakdown by engulfing EC and EC components (CD68⁺/CD31⁺ MG) (Jolivel et al., 2015). The expansion of vascular injury results in the extravasation of neutrophils and additional serum components, activating even more MG (Qiu et al., 2021). Injecting fibrinogen solution into the cerebral cortex of mice triggers a rapid MG response, which is characterized by MG aggregation around blood vessels, release of ROS, and enhanced MG migration (Jolivel et al., 2015). When fibrinogen binds to the integrin receptor, CD11b/CD18 activates downstream Akt and Rho signaling pathways, ultimately leading to MG activation (Jambrovics et al., 2023; Figure 2).

Figure 2.

Ischemia and hypoxia-induced BBB breakdown triggers the activation of MG.

BBB: Blood–brain barrier; MG: microglia; VEGF: vascular endothelial growth factor.

However, damage to the BBB and the activation of MG form a pernicious cycle. Activated MG can secrete various matrix-degrading enzymes, including MMPs and tissue proteases, also known as cysteine proteases (Lively and Schlichter, 2013). MMPs can induce the degradation of tight junction proteins, leading to BBB damage, as observed in VaD patients (Duits et al., 2015). Furthermore, a deficiency in tissue protease K levels exacerbates the activation of MG and the destruction of BBB in mice following focal cerebral ischemia (Zhao et al., 2019; Figure 2). Moreover, prolonged ischemia results in depleted oxygen (O₂) and ATP levels, subsequently increasing TNF-α levels (Li et al., 2020). Elevated secretion of inflammatory cytokines and the activation of nuclear transcription processes further contribute to upregulated MMP expression and worsened BBB damage (Feng et al., 2022). Notably, in the early stages of vascular injury, the chemokines secreted by ECs attract MG to the perivascular region, facilitating the maintenance of BBB integrity. Nevertheless, persistent damage induces the transition of MG from a protective to a detrimental phenotype, further compounding the BBB damage by releasing pro-inflammatory cytokines and phagocytosing the distal processes and axons of AS (Haruwaka et al., 2019).

Metabolic reprogramming

Metabolic reprogramming was originally posited as the process wherein malignant cells adapt and modify their metabolic pathways during proliferation. Whereas healthy cells typically derive energy through oxidative phosphorylation, tumor cells preferentially harness energy via glycolysis. They persist in generating ATP through glycolysis even under conditions with ample oxygen (Yang et al., 2022a). However, subsequent research has revealed that this phenomenon extends beyond tumor cells, manifesting in the onset and progression of various ailments. When confronted with ischemic and hypoxic environments, cells transition from aerobic to anaerobic metabolism, reducing the energy yield from 32 to 2 ATP molecules. This energy deficit triggers neuronal depolarization and substantial activation of specific glutamate receptors, precipitating an ischemic cascade reaction. To meet the amplified energy demand, the body initiates compensatory pathways, along with an array of metabolic reprogramming maneuvers, such as glycogen metabolism, lactate metabolism, amino acid metabolism, and lipid metabolism (Huang et al., 2024). This process leads to a sharp increase in ROS content, disrupting the antioxidant defense system and ultimately causing oxidative stress and localized inflammation (Lushchak et al., 2021). Consequently, metabolic reprogramming is considered to be a pivotal impetus for the inflammation mediated by MG (Sun et al., 2023). Experimental studies have demonstrated that modulating energy metabolism can notably ameliorate the inflammatory response of MG. Under conditions of ischemia and hypoxia, MG exhibit heightened expression of hypoxia inducible factor-1 and glycolysis-related proteins such as hexokinase 2, pyruvate kinase type 2, and glucose transporter protein (Borst et al., 2019; Figure 3). However, the use of glycolytic inhibitors (2-deoxy-d-glucose and 3-bromopyruvate), small interfering RNAs (siRNAs) targeting glucose transporter type 1 (Glut-1), and siRNAs targeting hexokinase 2 substantially inhibited the activation of lipopolysaccharide-induced nuclear factor kappa B (NF-κB) and AMP-activated protein kinase/mammalian target of rapamycin signaling pathways in MG. This was accompanied by a reduction in the release of the pro-inflammatory factors IL-1β and TNF-α (Cheng et al., 2021). Consequently, some scholars have advocated for the manipulation of metabolic reprogramming in MG as a promising approach for the treatment of ischemic diseases (Liang et al., 2021).

Figure 3.

Ischemia and hypoxia-induced metabolic reprogramming triggers the activation of MG.

ATP: Adenosine triphosphate; HK2: hexokinase 2; IL: interleukin; iNOS: inducible nitric oxide synthase; LDH: lactate dehydrogenase; MG: microglia; mTOR: mammalian target of rapamycin; NADPH: nicotinamideadenine dinucleotide phosphate; NO: nitric oxide; NOX: nicotinamide adenine dinucleotide oxidase; O₂: oxygen; PDH: phosphate dehydrogenase; PFK: phosphofructokinase-1; PI3K: phosphatidylin-ositol-3-kinase; PKM2: pyruvate kinase type 2; PPP: pentose phosphate pathway; ROS: reactive oxygen species; TCA: tricarboxylic acid.

However, the metabolic reprogramming triggered by ischemia and hypoxia appears to engage in a complex interplay with immune inflammation, creating a detrimental cycle (O’Neill et al., 2016). Under normal circumstances, MG predominantly rely on glycolysis and mitochondrial oxidative phosphorylation to meet their energy needs. However, after ischemia and hypoxia, glucose is metabolized into lactic acid, which is subsequently released into the extracellular space to cause lactic acidosis. Activated MG then release an abundance of pro-inflammatory mediators, including IL-1β, TNF-α, IL-6, iNOS, ROS, and NO. The release of these inflammatory mediators elicits substantial alterations in the tissue microenvironment, disrupting the original metabolic pathways of cells. When inflamed, activated immune cells urgently require sufficient energy and biomolecules to support their growth, proliferation, and the production of pro-inflammatory molecules. Consequently, this further augments glycolysis and activates the pentose phosphate pathway, leading to nicotinamide adenine dinucleotide phosphate (NADPH) production and promoting lipid synthesis, while oxidative phosphorylation and fatty acid oxidation remain suppressed (Planas, 2024). For instance, NO activation results in elevated levels of glucose-6-phosphate dehydrogenase, phosphofructokinase-1, and lactate dehydrogenase in BV2 cells, alongside an increase in lactate release. Thus, NO activation enhances glucose uptake in BV2 cells and facilitates its conversion to lactate. Inhibition of NO markedly reduces glucose consumption and lactate release (Gimeno-Bayón et al., 2014). Furthermore, the extensive release of ROS appears to induce mitochondrial damage in MG, with a significant decrease in mitochondrial damage observed upon ROS clearance (Simpson and Oliver, 2020; Figure 3). Therefore, regulating MG through the lens of energy metabolism may represent an effective strategy for the treatment of VaD, with specific details available in the referenced literature (Miao et al., 2023; Yu et al., 2023; Huang et al., 2024).

Protective Effects of Microglia Activated in the Early Stage of Vascular Dementia

The protective roles of MG can be categorized as follows: (1) Perception role: MG perform perpetual monitoring, utilizing close to 100 gene products, such as purinergic receptor P2Y12 (P2RY12), AXL receptor tyrosine kinase (AXL), and proto-oncogene tyrosine-protein kinase MER (MER), to detect alterations in the microenvironment. This allows them to survey the vicinity periodically, typically every few hours. Upon detecting tissue damage or infection, they promptly migrate to the affected area and initiate repair processes (Hickman et al., 2018). (2) Housekeeping role: MG express genes encoding chemokines and their receptors, phagocytosis-related genes (like scavenger receptor and Trem2), and genes involved in synaptic pruning and remodeling (including C1q and Cx3cr1), thereby completing tasks such as synaptic remodeling, migration to damaged sites, phagocytosis or clearance, and maintenance of myelin homeostasis (Hickman et al., 2018). (3) Defense role: MG express Fc receptors, Toll-like receptors, viral receptors, and antimicrobial peptides, allowing them to mediate the host’s defense against infectious pathogens, harmful autoproteins, and primary or metastatic CNS tumors. In response to these stimuli, MG trigger a neuroinflammatory reaction, producing inflammatory cytokines like TNF and IL-1 along with chemokines such as Ccl228, and simultaneously recruit additional cells and stimulate them to eliminate noxious substances, thereby preserving brain homeostasis (Hickman et al., 2018).

In the early stage of cerebral ischemia, MG are swiftly activated and migrate to the affected area, with the numbers of the predominant M2 type rising from day 1, peaking between days 5–7, and then gradually declining until day 42 (Jiang et al., 2020). The numbers of the M1 type also begin to increase on the first day, albeit at a lower level than those of the M2 type, peaking on day 14 and subsequently starting to wane. Notably, on day 7, both types are present in equal proportions, with M2 being the dominant type from day 1 to 7 and M1 predominating from day 7 (Jiang et al., 2020). This shift implies that during the initial phase of ischemia, MG are dominated by the anti-inflammatory M2 type, exerting beneficial anti-inflammatory effects (Hu et al., 2012). Specifically, M2-type MG upregulate the expression of receptors (including CD206 and CD163), cytoplasmic enzymes (such as arginase-1), and secreted proteins (such as YM1) and secrete anti-inflammatory cytokines such as IL-3, IL-4, IL-10, transforming growth factor-beta (TGF-β), and insulin-like growth factor-1 (IGF-1), which enhance phagocytic activity, rapidly eliminate cellular debris, and mitigate inflammation (Kwon and Koh, 2020; Figure 4). Meanwhile, in the aftermath of brain ischemia, neurons located in the core region undergo rapid degeneration and necrosis within a few minutes (Hou et al., 2020). Damaged neurons can stimulate MG to undertake neuroprotective roles post-ischemia, including phagocytosing injured neurons, clearing away cellular debris, and minimizing neurotoxicity (Xu et al., 2020). The phagocytic activity of MG toward neurons is tightly regulated by “eat me” or “don’t eat me” signals emitted by neurons. Upon detecting the former signal, MG promptly identify and phagocytose neurons displaying these signals (Cornell et al., 2022).

Figure 4.

Early protective effects of M2 type MG.

IGF-1: Insulin-like growth factor-1; IL: interleukin; M1: microglia type 1; M2: microglia type 2; MG: microglia; TGF-β: transforming growth factor beta; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

A recent review highlights the crucial protective role of MG in maintaining BBB integrity after ischemic injury (Ronaldson and Davis, 2020). As the first responders to vascular damage, MG near the microvasculature swiftly surround the damaged area in a purine receptor P2Y12-dependent manner and secrete substantial amounts of calcium adhesive protein E, thereby effectively sealing the “gap” in the BBB and facilitating its temporary reclosure (Lou et al., 2016). The temporary reclosure of the BBB helps maintain the integrity of the BBB in the early stage of vascular injury. Additionally, during the initial phase of vascular insult, ECs release the chemokine C–C chemokine ligand 5, which attracts MG to the site of injury (Haruwaka et al., 2019). These MG come into direct contact with the ECs and prevent the leakage of plasma components by upregulating the expression of tight junction protein claudin-5, further reinforcing the structural integrity of the BBB. However, during the ongoing inflammatory process, MG may engulf the end-feet of AS, leading to compromised BBB function (Haruwaka et al., 2019; Figure 4). Overall, these findings indicate the major protective effects of MG on the BBB during the early stage of ischemia (Gaire, 2022). Nevertheless, translating these protective effects into drug development poses a considerable challenge.

Continuously Activated Microglia Mediated Myelin Sheath Injury

Simpson et al. (2007) investigated MG in white matter lesions of the aging brain. Their study revealed that, in comparison with healthy elderly brains, brains with lesions showed pronounced aging-associated changes in the signal intensity surrounding the ventricles on magnetic resonance imaging (MRI). This indicated substantial myelin deterioration, which was concurrently accompanied by increased immune reactivity of MG. Thus, the presence of activated MG in white matter lesions may be closely correlated with the severity of these lesions. This assumption has been comprehensively substantiated through animal experiments. As mentioned earlier, on the first day post-bilateral carotid artery ligation in rats, immunofluorescence staining demonstrated a marginal, albeit statistically insignificant, elevation in the number of Iba1⁺ MG. This finding indicated activation of MG on the first postoperative day, which peaked on the third postoperative day, showing activation of approximately 86% of MG with marked statistical significance (Sun et al., 2021). Rats that underwent two-vessel occlusion (2VO) showed notable myelin deterioration on day 7 postoperatively (Zhang et al., 2020), and while indications of damage appeared as early as day 3, they were not yet important at this stage (Sun et al., 2021). However, the changes in the white matter damage score manifested later, becoming notable at day 14 postoperatively (Wang et al., 2023a). Thus, activation of MG precedes demyelination and may constitute a pivotal factor in myelin damage.

Long-term chronic hypoperfusion polarizes MG toward the M1 phenotype, which is characterized by elevated expression of M1 markers and reduced production of M2 markers (Xu et al., 2024). Furthermore, M1-type MG predominantly secrete copious amounts of pro-inflammatory cytokines, including TNF-α, IL-1β, IL-6, IL-16, and NO (Kwon and Koh, 2020), these factors are notably upregulated in rats with chronic hypoperfusion (Zhang et al., 2020a; Zhao et al., 2021; Figure 5). Xu et al. (2021) observed that TNF-α-targeted therapy with adalimumab significantly improved memory deficits in rats with VaD, mitigated neuronal loss in the hippocampus, reversed M1/M2 polarization, suppressed the neuroinflammatory NF-κB pathway, and inhibited oxidative stress. These findings suggest that the pro-inflammatory mediators released upon MG activation contribute to myelin damage and memory impairment in rats. On the flipside, the M1 phenotype of MG also leads to the production of elevated levels of enzymes that mediate inflammatory responses, such as COX-2. Reports have documented COX-2 overexpression at sites of demyelinating lesions in demyelinating animal models (Carlson et al., 2006; Kihara et al., 2009; Palumbo et al., 2011), indicating a potential link between COX-2 and myelin damage. COX, a rate-limiting enzyme in the arachidonic acid metabolism, exists in two subtypes: COX-1 and COX-2. Notably, COX-2 is predominantly expressed in regions of inflammation, tissue injury, and malignant transformation (Uzuegbunam et al., 2023). In a zebrafish demyelination model, Cao et al. (2020) observed that the administration of celecoxib, a selective COX-2 inhibitor, could prompt the phenotypic shift of MG from M1 to M2, thereby improving the inflammatory microenvironment, suppressing caspase-dependent apoptosis, and ultimately yielding therapeutic benefits against demyelination (Figure 5).

Figure 5.

Destructive effects of M1 type MG in the later stage.

AS: Astrocytes; C1q: complement 1q; COX-2: cyclooxygenase-2; IL: interleukin; iNOS: inducible nitric oxide synthase; MG: microglia; MDA: malondialdehyde; M1: microglia type 1; M2: microglia type 2; NO: nitric oxide; ROS: reactive oxygen species; TNF-α: tumor necrosis factor-α; VEGF: vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor.

Meanwhile, the M1 phenotype of MG also triggers severe oxidative stress. A rat model of VaD showed a notable increase in ROS and malondialdehyde levels, which was accompanied by a reduction in superoxide dismutase and glutathione levels (Hu et al., 2019). The release of these substances contributed not only to neuronal degeneration but also to axonal damage and demyelination (Chen et al., 2020; Dong et al., 2023). Numerous animal studies have demonstrated a close association between oxidative stress and white matter injury in hypoperfusion models (Chen et al., 2022; Rajeev et al., 2022; Shkirkova et al., 2024). This association may arise from the interaction of elevated ROS levels with NO to form peroxynitrite, a highly reactive free radical species that depletes circulating NO. NO is generated through the conversion of l-arginine to l-citrulline by nitric oxide synthase (NOS), which is aided by cofactors such as tetrahydrobiopterin (BH4). NOS exists in three subtypes: neuronal NOS (nNOS), iNOS, and endothelial NOS (eNOS), which are found in neurons, activated MG and AS, and microvessels, respectively. White matter is particularly vulnerable to vascular injury induced by chronic hypoperfusion (Bennett et al., 2009). Furthermore, under conditions of oxidative stress, the thioredoxin-interacting protein (TXNIP) binds to the active site of thioredoxin, leading to its oxidation. This process intensifies oxidative stress and activates the apoptosis signaling regulator protein 1-mediated signaling pathway (Yang et al., 2024). Additionally, TXNIP has been implicated in mediating and activating immune responses during excessive ROS production. Specifically, when TXNIP binds to NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), it triggers the activation of the NLRP3 inflammasome, leading to the secretion of IL-1β and causing the initiation of an inflammatory response that further compromises the function and integrity of myelin (Figure 5).

However, neuroinflammation triggered by activated MG may exacerbate damage to AS, given that MG activation and neuroinflammation can precede any changes in AS (Liu et al., 2020). Under normal physiological conditions, AS facilitates the formation and maintenance of myelin and BBB by eliminating extracellular ions and neurotransmitters, as well as releasing pre-myelinal factors. However, under low-perfusion conditions, activated MG secrete cytokines such as TNF-α, IL-1α, IL-6, IL-1β and complement 1q, which induce the formation of neurotoxic A1-type AS. This A1-type AS loses its capacity to promote neuronal survival, growth, synaptogenesis, and phagocytosis, ultimately leading to neuronal and oligodendrocyte demise (Lawrence et al., 2023). This neurotoxicity may stem from the binding of lipocalin-2, which is secreted by A1-type AS, to lipocalin-2 receptors (LCN2Rs) on MG and hippocampal neurons, causing indirect and direct neurotoxic effects (Tsai et al., 2024; Figure 5). Additionally, AS produce lactose ceramide (LacCer), which further fuels inflammation and neurodegenerative processes (Mayo et al., 2014). Although the intricate interplay between MG and AS in neurodegenerative disorders warrants a detailed discussion beyond the scope of this article, interested readers are encouraged to consult the referenced literature for a more comprehensive understanding (Kwon and Koh, 2020). On the other hand, appropriately activated MG and pro-inflammatory mediators secreted by AS can stimulate OPC, driving their proliferation, migration, and ultimate differentiation into mature OLs, which are crucial for myelin regeneration and repair. For detailed information, please refer to the literature (Nutma et al., 2020). However, excessive activation of MG results in the overproduction of pro-inflammatory mediators, ROS, free radicals, and other harmful compounds, which can impede the proliferation and differentiation of OPCs, and in extreme cases, even lead to their death (Rahimian et al., 2022). A recent study used 2VO to establish a CCH rat model and examined the sheath structure in the CC through Lucas rapid blue staining and MRI. The results showed that long-term CCH led to demyelination and structural disorder of the CC, as well as damage to white matter fiber bundles in the CC and optic tract, indicating that VaD affects cognition by destroying axons and myelin sheaths (Niu et al., 2020).

Potential Biomarkers for Vascular Dementia

TREMs are a novel category of pattern-recognition receptors that were recently shown to exhibit widespread expression in various cell types, including granulocytes, monocytes, tissue macrophages, dendritic cells, MG, and osteoclasts. Additionally, they are present on the surfaces of natural killer cells, B cells, T cells, epithelial cells, and ECs, underscoring the pivotal role of the TREM family in regulating innate immunity. These receptors are intricately linked to inflammatory responses, neurodegenerative disorders, bone remodeling, metabolic syndrome, atherosclerosis, and cancer (Colonna, 2023). The existing research on the TREM family has predominantly focused on TREM1 and TREM2.

TREM2

Since TREM2 is predominantly expressed in MG within the brain, it has been posited to be a crucial indicator for discerning the transition of MG from a quiescent state to a disease-activated state (McQuade et al., 2020). TREM2 is primarily composed of three distinct segments: the extracellular, transmembrane, and intracellular segments (Bharadwaj et al., 2024). The extracellular segment encompasses an immunoglobulin-like (Ig-like) domain, which serves as a pivotal region for the recognition of and binding to various ligands. These ligands include PAMPs, DAMPs, as well as specific biomolecules such as amyloid-beta (Aβ), ApoE, and phospholipids. This structural domain empowers TREM2 to detect and respond to diverse alterations in the intracellular and extracellular milieu. The transmembrane segment anchors TREM2 to the cell membrane, ensuring its stable localization on the cell surface and facilitating effective signal transduction. Specific residues within the transmembrane segment also engage in binding to adapter proteins such as DAP12 and DAP10, which are subsequently phosphorylated and activated. DAP12 primarily mediates the activation of splenic tyrosine kinase (SYK), while DAP10 enhances signal propagation by recruiting signaling molecules such as phosphatidylinositol 3-kinase (PI3K). Although the intracellular segment of TREM2 is relatively small, it activates downstream signaling pathways through its binding to DAP12 and DAP10. The activated signaling molecules, including SYK and PI3K, further initiate a cascade of signaling pathways, such as activation of phospholipase Cγ2, the PI3K signaling pathway, the mammalian target of rapamycin, and mitogen-activated protein kinase (Deczkowska et al., 2020). These signaling pathways ultimately influence the phagocytic function, survival, metabolic equilibrium, and inflammatory response of cells (Cui et al., 2021).

A recent investigation identified a distinct subset of MG within the white matter of elderly mice, which was termed white matter-associated MG. These cells are age-dependent, reliant on TREM2 signaling, and localized in nodules responsible for clearing myelin debris from the white matter (Safaiyan et al., 2021). DAP12 can also regulate the ability of MG to engulf apoptotic cells and myelin debris by weakening the transmission of the runt-related transcription factor 1 (RUNX1), signal transducer and activator of transcription 3 (STAT3), or transforming growth factor-β pathways, promoting myelin repair (Zhou et al., 2023). Thus, TREM2 is crucially implicated in the clearance of myelin debris. However, TREM2 also plays a pivotal role in myelin regeneration, as evidenced by impaired myelin regeneration following copper treatment in Trem2-knockout mice (McCray et al., 2024). This phenomenon may be attributed to the activation of antibody-dependent TREM2 on MG, which enhances the density of oligodendrocyte precursors in demyelinated areas and promotes the formation of mature OLs, facilitating myelin regeneration and preserving axonal integrity (Cignarella et al., 2020). Nevertheless, the extracellular domain of TREM2 can undergo cleavage by members of the disintegrin metalloproteinase family, leading to the release of a soluble TREM2 fragment detectable in peripheral plasma and serum (Yin et al., 2024).

A considerable amount of research has focused on soluble TREM2 as a potential biomarker. In patients with VaD, a notable decrease in serum TREM2 levels is regarded as an independent risk factor for cognitive impairment. Overexpression of TREM2 significantly inhibits M1 polarization in MG by reducing the expression levels of iNOS and pro-inflammatory cytokines. Conversely, TREM2 overexpression also enhances M2 polarization in MG by increasing the expression levels of arginase-1 and anti-inflammatory cytokines (Wang et al., 2020a). TREM2 downregulates TLR4 signaling and negatively regulates downstream NF-κB pathway activation, slowing down the occurrence of neuroinflammatory responses (Ren et al., 2018). These results strongly suggest that TREM2 provides protective effects in VD by regulating the phenotype of activated MG and may serve as a novel potential therapeutic target for VD. However, some studies have provided conflicting findings; one study reported a significant increase in the age- and sex-adjusted incidence rate of VaD with elevated serum TREM2 levels (Ohara et al., 2019). Patterns of early increase followed by a late decrease in soluble TREM2 levels were particularly prevalent among patients showing ischemic stroke with poor prognoses (Kwon et al., 2020). Moreover, higher plasma levels of soluble TREM2 have been associated with an increased risk of cognitive impairment post-stroke (Zhu et al., 2022). These discrepancies in findings may stem from differences in participant characteristics, methodologies for data collection, biomarker detection protocols, and statistical analyses (Moqri et al., 2024). Recent advancements in Mendelian randomization analysis techniques have garnered attention in this regard, revealing a considerable causal link between peripheral TREM2 levels and AD (z-score = –7.495, P-value = 6.61 × 10^–14) (Liu et al., 2024). Concurrently, our recent research has identified a significant elevation in serum TREM2 levels in 2VO rat models of VaD, with serum TREM2 levels showing a marked negative correlation with their learning and memory capabilities. However, Mendelian randomization analysis did not show a causal relationship between serum TREM2 levels and VaD in our study (unpublished data).

TREM1

Similar to TREM2, TREM1 consists of three structural components: a brief cytoplasmic tail, a transmembrane segment, and an immunoglobulin-like domain. TREM1 possesses the ability to bind to a variety of molecules, including platelets, peptidoglycan recognition protein 1, high mobility group protein 1, and heat shock protein 70. Upon binding to TREM1, these ligands initiate the primary phase of signal transduction. The complex formed by the stable interaction of DAP12 with its cytoplasmic tail, which is facilitated by unique electrostatic interactions, constitutes the essential functional unit of signal transduction. DAP12 harbors an immune receptor tyrosine activation motif. When TREM1 engages with its ligand, the I immune receptor tyrosine activation motif of DAP12 undergoes phosphorylation, prompting phosphorylated DAP12 to recruit and activate protein tyrosine kinases, such as SYK, and thereby enhancing the recruitment and tyrosine phosphorylation of adaptor complexes, including Cbl, SOS, and GRB2. These adaptor complexes facilitate downstream signal transduction through pathways such as PI3K, PLCγ, and ERK. Such pathways induce Ca²⁺ mobilization, reorganize the actin cytoskeleton, and activate transcription factors, including Elk1, NFAT, AP-1, c-Fos, c-Jun, and NF-κB. The activated transcription factors encode pro-inflammatory cytokines, chemokines, and cell surface molecules, orchestrating cellular immune responses and inflammatory reactions (Zhang et al., 2022). Furthermore, the TREM1-induced activation of the PI3K and ERK pathways induced by TREM1 can also enhance cell survival by inactivating pro-apoptotic factors. The activation of the TREM1 signaling pathway engenders various alterations in cellular phenotype and function, which hold major implications for the regulation of immune responses and the onset and progression of diseases.

TREM1, as a pivotal regulator of inflammation, has been identified as a crucial participant in the pathogenesis of diverse inflammatory conditions, encompassing infectious and non-infectious diseases such as bacterial and fungal infections, sepsis, pancreatitis, ischemia-reperfusion injury, colitis, fibrosis, atherosclerosis, autoimmune disorders, cancer, and the tumor microenvironment (Li et al., 2024). Similar to TREM2, the extracellular segment of TREM1 is produced and released as soluble TREM1. Soluble TREM1 primarily arises from the translation of a TREM1 mRNA splice variant lacking the sequence encoding the transmembrane and cytoplasmic regions of TREM1. Consequently, some scholars have posited that soluble TREM1 can serve as a biomarker for cancer and infectious diseases such as sepsis and septic shock (Li et al., 2024). This notion is also gradually gaining traction in the context of neurodegenerative diseases. Shi et al. have reported a correlation between elevated plasma soluble Trem1 levels and AD (odds ratio [OR] per one standard deviation [SD] increase = 1.064; 95% CI: 1.012–11.119; P = 0.014; PFDR = 0.056) (Shi et al., 2022). Similarly, our study yielded parallel results, establishing a considerable association between increased serum TREM1 levels and impaired learning and memory in 2VO rats. Additionally, MR analysis revealed a meaningful causal link between serum TREM1 levels and VaD, demonstrating a positive correlation (unpublished data).

In summary, TREM, as a pivotal transmembrane receptor protein, holds paramount significance in preserving the equilibrium of the CNS, modulating immune responses, and engaging in lipid metabolism. Its intricate structural attributes endow it with the capacity to discern and affix to a myriad of ligands, thereby initiating intricate signal transduction cascades. The activation of the TREM signaling pathway elicits profound transformations in cellular phenotype and function, which are crucial for mitigating pathological insults and safeguarding tissue homeostasis. Recent scholarly endeavors propose that soluble TREM1 or TREM2 may serve as promising biomarkers for VaD or age-related cognitive decline. This will provide strong reference data for the diagnosis and prevention of such diseases, but a large amount of research is still needed to confirm this conclusion. In the future, with in-depth studies of the TREM signaling pathway mechanism, more targeted therapeutic drugs and methods for TREM can be developed, thereby presenting novel avenues and tactics for tackling recalcitrant conditions like VaD and cancer.

Therapeutic Drugs for Microglia and Myelin Damage

Currently, despite the absence of an effective treatment modality for CNS myelin damage in clinical practice, domestic and international studies have dedicated substantial efforts toward the development of drugs to address myelin damage. A range of drugs that aim to prevent myelin damage or facilitate its repair have been synthesized and classified on the basis of their distinct mechanisms (Tables 1 and 2). Currently, many drugs are targeted toward glial cells (OLs, their precursor cells, MG, and AS), which may represent an effective approach to treating this category of diseases. Interestingly, numerous pharmacological agents that are primarily administered for conditions not precipitated by chronic cerebral ischemia have shown remarkable ability to effectively prevent or ameliorate myelin damage. In this regard, our comprehensive review may offer valuable insights for the development of existing and novel drugs.

Table 1.

Drugs related to MG for treating CNS myelin sheath injury

Drug	Mechanism	Disease	Current stage	Reference
rHIgM22	Promotes remyelination by recruitment of MG and phagocytosis of myelin debris; stimulates OPC proliferation and remyelination	MS	Clinical trial	Greenberg et al., 2022
Colony-stimulating factor 1 receptor inhibitor	Consumes MG in CNS to reduce myelin damage	Solid tumors	Clinical trial	Kang et al., 2023
Tuftsin	Increases immunosuppression by shifting MG to a distinctly anti-inflammatory phenotype, enhancing Th2 response, and limiting Th1 response	EAE	Experimental study	Thompson et al., 2018
AL002	An agonist of TREM2, AL002 can activate downstream effector Syk phosphorylation, ultimately leading to MG proliferation	AD	Clinical trial	Wang et al., 2020b
ATV:TREM2	TREM2-activating antibodies, harnessing BBB transporters, can invigorate MG metabolism	AD	Experimental study	van Lengerich et al., 2023
Nangibotide	a TREM1 inhibitor	Septic shock	Clinical Trials	François et al., 2023
LP17	a TREM1 inhibitory peptide	Ischemic stroke	Experimental Study	Xu et al., 2019

AD: Alzheimer's disease; BBB: blood–brain barrier; CNS: central nervous system; EAE: experimental allergic encephalomyelitis; MG: microglia; MS: multiple sclerosis; OPC: oligodendrocyte precursor cell.

Table 2.

Drugs unrelated to MG for treating myelin sheath injury in the central nervous system

Drug	Mechanism	Disease	Current stage	Reference
Research and development for astrocytes
Anti-aquaporin-4 monoclonal antibody blocker	Anti-aquaporin-4 monoclonal antibody blocker prevents astrocyte damage, thereby reducing neuroinflammation and myelin damage.	NMOSD	Clinical trial	Yamamura et al., 2019
Research and development for OLs
Opicinumab	Opicinumab stimulates OPCs to differentiate into OLs and increases myelin protein synthesis.	MS	Clinical trial	Cadavid et al., 2019
Olesoxime	Olesoxime has neuroprotective effects and promotes OPC differentiation and enhances myelination.	Spinal muscular atrophy	Clinical trial	Bertini et al., 2017
Quetiapine	Quetiapine as a nonselective GPCR antagonist, enhances OL regeneration and myelin repair.	Anxiety and depression	Clinical trial	Ravindran et al., 2022
GNbAC1	GNbAC1 as a monoclonal antibody against the envelope protein of human endogenous retrovirus promotes the differentiation of OPC.	MS	Clinical trial	Hartung et al., 2022
Nimodipine	Nimodipine improves survival of mature OLs, more myelinated axons, and functional recovery.	Vascular dementia	Clinical trial	Zongfang et al., 2020
Research and development for inflammation
Glycyrrhizin	Glycyrrhizin dampens inflammation and promotes oligodendrogenesis likely through peripheral T cell modulation.	MS	Clinical trial	Ford et al., 2022
VX15 (Vaccinex)	An anti-SEMA4D monoclonal antibody, Vaccinex potentially targets inflammatory mechanisms causing demyelination, as well as influencing the capacity of OPCs to contribute to remyelination.	Autoimmune encephalomyelitis	Clinical trial	Okuno et al., 2010
Klotho	Klotho promotes OPC maturation through extracellular signal-regulated kinase and Akt (protein kinase B).	Neurodegenerative disorder	Experimental study	Torbus-Paluszczak et al., 2018
Research and development for oxidative stress
Dimethyl fumarate	Dimethyl fumarate reduces inflammation and oxidative stress via Nrf2-dependent antioxidative pathways.	MS	Clinical trial	Svenningsson et al., 2022
Research and development for histamine
GSK239512	H3 receptor antagonist, GSK239512 enhances remyelination.	MS	Clinical trial	Schwartzbach et al., 2017
Clemastin	As an H1 histamine receptor antagonist and M1/M3 muscarinic receptor reverse antagonist, clemastin promotes OPC differentiation and enhances myelination.	MS	Clinical trial	Green et al., 2017
Research and development for ATP
Biotin	Biotin increases the production of myelin by increasing ATP production and stimulating fatty acid synthesis.	MS	Clinical trial	Cree et al., 2020
Research and development for dopamine
Domperidone	A D2/D3 dopamine receptor antagonist, domperidone can increase the content of prolactin and further promote the regeneration of myelin.	MS	Clinical trial	Koch et al., 2021

CNS: Central nervous system; GPCR: G protein-coupled receptor; MG: microglia; MS: multiple sclerosis; NMOSD: neuromyelitis optica spectrum disorder; OL: oligodendrocyte; OPC: oligodendrocyte precursor cell.

Schampel et al. observed that the antihypertensive drug nimodipine selectively induces IBA1⁺ cell apoptosis in experimental autoimmune encephalomyelitis, a self-immune-mediated demyelination mouse model akin to MS, spinal cord explants, and MG cell lines. This drug also enhanced the survival rates of mature OLs and myelinated axons and improved functional recovery. Another example is domperidone, a dopamine 2 receptor antagonist that shows antiemetic and prokinetic effects through activation of chemoreceptors and motor function in the stomach and intestines for treating gastric stasis and any disease that causes chronic nausea and vomiting. Domperidone can trigger prolactin release, which can regulate OL precursor proliferation and repair myelin damage. Therefore, some recent studies have explored the use of domperidone for treating MS. Although the results were not entirely satisfactory, patients with high prolactin levels showed a significantly lower risk of disability progression. This observation provides valuable ideas for further research (Koch et al., 2021). Simvastatin is a lipophilic statin with a short half-life, which was originally employed to treat hypercholesterolemia before finding widespread application in various conditions such as coronary heart disease, stroke, and diabetes. Given the effectiveness of statins in lowering cholesterol levels and the brain being the richest source of cholesterol, with myelin accounting for 70% of the total brain cholesterol, simvastatin has been recently used to treat disorders associated with myelin damage, demonstrating promising therapeutic outcomes. Wang et al. (2023b) observed that simvastatin can ameliorate the development of inflammatory demyelination in MS and restore remyelination in experimental autoimmune encephalomyelitis, possibly through its ability to promote OL progenitor cell survival and differentiation. Nonetheless, the potential mechanisms underpinning the therapeutic effects of statins in myelin damage remain ambiguous and warrant further elucidation.

Recent studies have also shown a substantial expansion in the realm of pharmaceuticals directed toward TREM2. Alector and AbbVie together generated a humanized monoclonal antibody, AL002, which possesses the ability to bind with TREM2 and thereby activate phosphorylation of the downstream effector SYK, ultimately eliciting MG proliferation (Song et al., 2022). Notably, AL002 has successfully passed the first phase of trials, encompassing 51 healthy individuals and 16 AD patients. Throughout the 12-week post-administration follow-up, all participants exhibited commendable safety profiles and tolerability, with no severe adverse events attributed to the highest administered dosage (Wang et al., 2020b). Presently, AL002 is advancing into a Phase II trial. This trial is expected to include approximately 328 participants, including patients with AD, and will aim to assess the efficacy and safety of AL002 in patients showing mild cognitive impairment and mild dementia attributable to AD (https://clinicaltrials.gov/study/NCT04592874). Parallelly, another noteworthy anti-TREM2 antibody, DNL919, has undergone rigorous evaluations pertaining to safety, tolerability, pharmacokinetics, and pharmacodynamics in healthy cohorts (https://clinicaltrials.gov/study/NCT05450549). Unfortunately, no relevant data has been published yet. However, on August 8, 2023, Denali announced the cessation of collaborative development efforts with Takeda pertaining to DNL919, as stated in a press release. The release elaborated that DNL919 had altered multiple biomarkers of MG, encompassing CSF1R, SPP1, IL1RA, IP10, MIP1b, and MCP-1, indicating target engagement. While the intervention did not elicit any severe adverse reactions, it did precipitate moderate, yet reversible, hematological alterations at the highest dosage tested. A news report quoted Denali executives who said the antibody caused anemia (https://www.alzforum.org/therapeutics/dnl919). Vigil, too, has contributed to this burgeoning field with VG-3927, a small-molecule TREM2 agonist designed to tackle neurodegenerative disorders rooted in dysfunction of MG. This innovative drug transcends the BBB, effectively activating TREM2’s downstream signaling cascade and modulating the activation and functioning of MG. Currently, VG-3927 is navigating through phase I clinical trials, which aim to validate its safety and tolerability in the treatment of AD (https://investors.vigilneuro.com/news-releases/news-release-details/vigil-neuroscience-announces-first-participant-dosed-phase-1). Moreover, the exploration of TREM2 agonists transcends these boundaries (https://www.alzforum.org/news/conference-coverage/antibodies-against-microglial-receptors-trem2-and-cd33-head-trials). For instance, TREM2-activating antibodies (ATV: TREM2) harnessing BBB transporters have demonstrated the ability to invigorate the metabolism of MG in AD models, encompassing proliferation augmentation and improvements in mitochondrial and glucose metabolism (van Lengerich et al., 2023). Conversely, the pursuit of TREM1-targeted therapies remains in its nascent stages, particularly in the context of neurodegenerative disorders. Nangibotide, a TREM1 inhibitor, has undergone double-blind, randomized phase 2 trials in septic shock patients, but its influence on neurodegenerative pathologies remains elusive (François et al., 2023). Another noteworthy contender, LP17 (LQFTDSGLYRCVIYHPP), a TREM1 inhibitory peptide, has shown great promise in ameliorating ischemic stroke-induced infarction, neuronal damage, and neuroinflammation, while simultaneously enhancing hippocampal cell proliferation and synaptic plasticity (Xu et al., 2019). TREM1 inhibitors present a promising avenue for therapeutic intervention in neurodegenerative diseases, stroke, and even tumors, but they require extensive foundational research and additional clinical trials to ascertain their efficacy, an important, yet challenging, endeavor.

The application of drugs requires rigorous scientific validation through fundamental experiments, as some drugs may even lead to worse outcomes despite targeting the same disease. For example, haloperidol, a first-generation typical antipsychotic drug, is effective in alleviating positive symptoms of schizophrenia. One study showed that treating adult male mice with haloperidol (2 mg/kg·d) for 30 days significantly reduced the expression of genes related to myelin/OL cells, including myelin basic protein, myelin proteolipid protein, myelin-associated glycoprotein, transferrin, UDP-galactose ceramide galactosyltransferase, and claudin-11. Thus, haloperidol can promote the proliferation of OPCs but inhibit their differentiation (Ren et al., 2013). For patients who require long-term treatment, balancing the efficacy of drugs with potential side effects represents a serious challenge for clinical translation. Similarly, olanzapine, an atypical antipsychotic drug, can also stimulate the proliferation of OPCs, but it also inhibits their differentiation due to increased or decreased phosphorylation of ERK1/2 (Ren et al., 2013). Notably, the antipsychotic medication quetiapine has shown promising effects in the repair of myelin damage. As a second-generation antipsychotic drug, quetiapine can bind to multiple neurotransmitter receptors, exhibiting high affinity for serotonin (5-HT) and dopamine receptors. It activates 5-HT1A receptors while exerting inhibitory effects on 5-HT2A receptors, promoting dopamine release and stimulating the patient’s nervous system, and effectively ameliorating depressive symptoms. However, the potential of this medication extends beyond the treatment of psychiatric disorders. With advances in scientific technology and a deeper understanding of the mechanisms of myelin damage, scientists have discovered that quetiapine can promote the differentiation of neural precursor cells into OLs by activating ERK1/2, facilitating MBP synthesis and myelin formation (Ren et al., 2013). This discovery opens up a new avenue for treating myelin damage and offers insights for the development of new therapeutic agents. Unfortunately, no clinical reports or studies have investigated the therapeutic effects of quetiapine on myelin damage-related disorders, despite preclinical evidence for its protective mechanisms for myelin. Biotin, a water-soluble vitamin, serves as a prosthetic group of carboxylases. In addition to its role as carboxylase prosthetic group, biotin also modulates gene expression and exerts a wide-ranging influence on bodily processes. High-dose biotin treatment has been shown to treat severe neurological diseases and slow the progression of MS (Sedel et al., 2016). While biotin can promote myelin regeneration by enhancing phospholipid formation in OLs, it can also enhance brain energy production, thus protecting demyelinated axons from degradation (Sedel et al., 2016). However, this conclusion remains controversial. In a randomized double-blind controlled trial, Cree et al. (2020) found that high-dose biotin (MD1003) did not significantly improve disability or walking speed in patients with progressive MS (SPI2), leading the authors to not recommend the use of MD1003 for the treatment of progressive MS. Thus, while the drug has shown positive effects in animal models or in vitro experiments, the same effects may not be achieved in humans. This further illustrates the importance of the clinical trial phase.

In summary, although the above-mentioned therapeutic agents have shown positive results in laboratory and early clinical trials, their clinical application prospects and limitations remain uncertain. More research, including larger-scale, longer-duration clinical trials as well as in-depth basic scientific research, is required to better understand the potential of these drugs and to ensure the safety and effectiveness of new therapies. Moreover, individual differences, drug interactions, and other potential side effects also require consideration to provide the most suitable treatment plan for patients.

Limitations

Although modern technology has advanced our understanding of myelin development in the CNS, the myelin proteome has been found to contain nearly 700 proteins (Rai et al., 2021), yet current research primarily focuses on high-abundance proteins. However, the roles of trace proteins in myelin formation, growth, maintenance, and repair remain largely unknown, and it is unclear whether they play a critical role. Addressing these gaps will be an important challenge for future research. Additionally, the mechanisms underlying myelin damage require further elucidation. As the main glial cells in the CNS, OLs, AS, and MG are involved in the formation and degradation of myelin, yet their specific roles and interactions in these processes remain incompletely understood. It has been demonstrated that neuroinflammation can cause changes in myelin. Despite these major challenges, additional information regarding the mechanisms of myelin formation may further clarify the role of myelin in CNS diseases and even psychiatric disorders, potentially facilitating the development of new therapies for related diseases.

Due to the protracted nature of CCH, patients may begin to exhibit symptoms only after the optimal window for treatment initiation has passed. Therefore, regular screening for high-risk patients can be considered to be the cornerstone for preventing the onset of such diseases. Emerging imaging techniques, such as positron-emission tomography and single-photon emission computed tomography, alongside high-resolution MRI, hold promise in addressing some of these challenges. These methods will facilitate the development of new biomarkers, which are pivotal for identifying patients at risk, staging disease progression, and assessing treatment outcomes. Ultimately, these improvements will allow early detection and intervention, paving the way for improved outcomes in the management of CCH-induced VaD.

Discussion

VaD, the second-most common type of dementia, imposes a heavy burden on the health and well-being of the elderly, and has implications for socio-economic development. Although numerous risk factors for VaD have been identified, the pathological mechanisms underlying this disease require elucidation. As a result, no definitive and effective drugs are currently available for treating VaD; existing medications are used on the basis of their therapeutic effects on specific prominent pathological manifestations (Morgan and McAuley, 2024). This review focused on the substantial myelin sheath injury observed in VaD as a key area of research and explored the various effects of MG on myelin sheath injury during disease progression. Additionally, it organized the drugs that may aid in myelin repair through MG-dependent and MG-independent mechanisms, thereby opening new research directions for the future treatment of VaD.

The primary role of MG is to preserve brain homeostasis and ensure proper functioning of the brain. In VaD, MG exhibit beneficial and detrimental effects. They engage in protective activities, such as phagocytosing cellular debris and maintaining the integrity of the BBB (Ronaldson and Davis, 2020). However, activated MG can also release pro-inflammatory factors and products of oxidative stress, which can further compromise the BBB and exacerbate neuroinflammation, ultimately leading to neuronal loss and myelin damage (Xu et al., 2021). As MG can polarize into distinct phenotypes that play varying roles at different pathological stages, relying solely on a single approach (such as anti-inflammatory or antioxidant therapy) for treating chronic ischemic injury may not yield optimal results. The effectiveness of such treatments can be influenced by the duration of ischemia and the specific functional role of MG at each stage. Therefore, to achieve ideal therapeutic outcomes, a comprehensive understanding of the entire process of brain injury caused by chronic ischemia, including the phenotypic changes and functional characteristics that occur following activation of MG, is essential. In conclusion, to effectively address the complexities of chronic ischemic brain injury, any future therapeutic strategies should take into account the duration of ischemia and the diverse effects of MG. Treatment of VaD presents major challenges at present. Although animal models of white matter injury have fully demonstrated the effects of BBB disruption, oxidative stress, and neuroinflammation, treatments based on these pathogenic mechanisms have thus far proven unsuccessful. Consequently, no effective therapeutic drugs are currently available for the entire range of injuries associated with VaD (Rajeev et al., 2023). Nevertheless, the synthesis and classification of these drugs offer valuable guidance for clinical medication. While quetiapine has been primarily used to treat psychosis, recent findings suggest it also has a positive effect on repairing myelination damage. This discovery paves the way for clinical applications of drug combinations or expansions and the development of new drugs. Nevertheless, to gain a deeper understanding of the pathogenesis of these diseases and the progression of myelination damage, identification of the pathophysiological processes involved is essential. A thorough exploration of the role and impact of myelination disorders in these diseases will enable the development of more targeted and effective treatment strategies. Moreover, identification of more effective drug treatment options is crucial. Given the diverse etiologies and pathological processes underlying these diseases, development of different drugs and treatment regimens that specifically target the underlying mechanisms may be required. For example, while improving cerebral blood supply is essential in VaD, the development of drugs that can repair damage to the myelin sheath of nerve fibers is also critical. Such targeted therapies have the potential to significantly improve prognosis.

Funding Statement

Funding: This work was supported by the Natural Science Foundation of Beijing, No. 7232279 (to XW); the National Natural Science Foundation of China, No. U21A20400 (to QW); Key Project of Beijing University of Chinese Medicine, Nos. 2022-JYB-JBZR-004 (to XW), 2024-JYB-JBZD-043 (to CL).

Data availability statement:

Not applicable.