Regulation of synaptic function and lipid metabolism

Abstract

Synapses are key structures involved in transmitting information in the nervous system, and their functions rely on the regulation of various lipids. Lipids play important roles in synapse formation, neurotransmitter release, and signal transmission, and dysregulation of lipid metabolism is closely associated with various neurodegenerative diseases. The complex roles of lipids in synaptic function and neurological diseases have recently garnered increasing attention, but their specific mechanisms remain to be fully understood. This review aims to explore how lipids regulate synaptic activity in the central nervous system, focusing on their roles in synapse formation, neurotransmitter release, and signal transmission. Additionally, it discusses the mechanisms by which glial cells modulate synaptic function through lipid regulation. This review shows that within the central nervous system, lipids are essential components of the cell membrane bilayer, playing critical roles in synaptic structure and function. They regulate presynaptic vesicular trafficking, postsynaptic signaling pathways, and glial–neuronal interactions. Cholesterol maintains membrane fluidity and promotes the formation of lipid rafts. Glycerophospholipids contribute to the structural integrity of synaptic membranes and are involved in the release of synaptic vesicles. Sphingolipids interact with synaptic receptors through various mechanisms to regulate their activity and are also involved in cellular processes such as inflammation and apoptosis. Fatty acids are vital for energy metabolism and the synthesis of signaling molecules. Abnormalities in lipid metabolism may lead to impairments in synaptic function, affecting information transmission between neurons and the overall health of the nervous system. Therapeutic strategies targeting lipid metabolism, particularly through cholesterol modulation, show promise for treating these conditions. In neurodegenerative diseases such as Alzheimer’s disease, Parkinson disease, and amyotrophic lateral sclerosis, dysregulation of lipid metabolism is closely linked to synaptic dysfunction. Therefore, lipids are not only key molecules in neural regeneration and synaptic repair but may also contribute to neurodegenerative pathology when metabolic dysregulation occurs. Further research is needed to elucidate the specific mechanisms linking lipid metabolism to synaptic dysfunction and to develop targeted lipid therapies for neurological diseases.

Introduction

Synapses, asymmetric cellular connections facilitating rapid point-to-point transmission of information from presynaptic neurons to postsynaptic cells, are vital components of neural circuits (Petzoldt and Sigrist, 2014; Cui et al., 2025; Liu et al., 2025). Both chemical and electrical synapses transmit neural impulses. Chemical synapses do so via neurotransmitters, whereas electrical synapses use gap junction channels to directly pass electrical signals between adjacent cells. In the central nervous system (CNS), most synapses are chemical, enabling a diverse range of neuronal responses. Structurally, synapses consist of presynaptic terminals, postsynaptic structures, and a synaptic cleft typically measuring 15–20 nm in width. Bidirectional signaling between presynaptic and postsynaptic structures regulates synaptic properties, including neurotransmitter type, release probability, postsynaptic receptor composition, and the presence of neuromodulator receptors (Grant and Fransén, 2020). This regulatory mechanism allows synapses to adapt to environmental changes, facilitating flexible information processing and storage within neural networks (Südhof, 2018).

Lipids show extensive structural diversity, varying across organisms, cell types, organelles, and membranes (Tatsuta et al., 2014; Skotland and Sandvig, 2022). Lipids such as phosphoinositides, sphingolipids, and cholesterol constitute the structural lipids of synapses, playing crucial roles in regulating signaling, synaptogenesis, neurogenesis, neurite growth, and long-term potentiation (LTP), which are essential for neural regeneration (Yang et al., 2017). Lipid rafts are dynamic nanoscale assemblies enriched in sphingolipids, cholesterol (Brown and London, 1998), and glycophosphatidylinositol-anchored proteins, contributing to G-protein-coupled receptor (GPCR) signaling, receptor clustering, and ionotropic receptor localization (Lemel et al., 2021). These structures orchestrate various signaling pathways critical for neuronal function and development (Simons and Toomre, 2000). Preserving synaptic physiological function hinges substantially on lipid molecules. Furthermore, lipid dysregulation has been increasingly associated with various CNS disorders, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Huntington’s disease, Parkinson’s disease (PD), and psychiatric disorders (Kao et al., 2020; Dai et al., 2021). A previous study focused on the role of individual lipids in specific neurological diseases (Yang et al., 2022). However, synapses, as connection points between neurons, are crucial in the pathogenesis of various neurological disorders. The proper functioning of synapses is directly linked to the overall health of the nervous system. Studying the impact of various lipids on synaptic function can offer new insights and therapeutic strategies for understanding neurological diseases.

In this review, we delve into the mechanisms through which lipids regulate synaptic activity within the CNS. We focus on the pivotal role of lipids in synaptic formation, neurotransmitter release, and signaling, while also exploring their involvement in synaptic regulation by glial cells. These mechanisms include astrocyte-neuron metabolic coupling, microglial synaptic phagocytosis, and oligodendrocyte myelination of neurons. We also discuss the implications of lipid dysregulation in synaptic damage associated with neurodegenerative diseases, offering insights into potential therapeutic strategies (Figure 1). By elucidating the physiological mechanisms underlying normal neurological function and the pathogenesis of diseases, this review provides a novel perspective on understanding synaptic regulation and dysfunction. Figure 2 presents a timeline highlighting key lipids involved in synaptic function.

Figure 1.

Key lipids regulate synaptic function and neurological diseases.

The function of synapses and their connections with microglia, astrocytes, and oligodendrocytes are closely linked to lipid regulation. Sterols, glycerophospholipids, sphingolipids, and fatty acids play crucial roles in this process. They regulate the release of synaptic vesicles, the function of postsynaptic receptors, synaptic phagocytosis, and cellular energy metabolism. Dysregulation of lipid metabolism is closely associated with synaptic pathologies related to various neurological disorders. For example, in Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and psychiatric disorders, abnormalities in lipid metabolism may lead to impairments in synaptic function, thereby affecting information transmission between neurons and the overall health of the nervous system. Created with Figdraw.com.

Figure 2.

Timeline of lipid research in synaptic function.

CNS: Central nervous system; DHA: docosahexaenoic acid; PUFA: polyunsaturated fatty acid; S1P: sphingosine-1 phosphate; SCFA: short-chain fatty acid; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; Syt: synaptotagmin.

Search Strategy

A computerized online search of the PubMed database was conducted to retrieve articles published up to September 31, 2024. A combination of the following text words (MeSH terms) was used to maximize search specificity and sensitivity: “lipid,” “synapse,” “cholesterol,” “sphingolipids,” “fatty acids,” “phospholipids,” “lipid rafts,” “astrocytes,” “oligodendrocytes,” “microglia,” “Alzheimer’s disease,” “Parkinson’s disease,” “amyotrophic lateral sclerosis,” “traumatic brain injury,” “ischemic brain injury,” “aging,” and “therapy.” For instance, when searching for the relationship between cholesterol and synapse, we entered “cholesterol” and “synapse” into the PubMed search box. The results were subsequently screened by title and abstract, and only studies exploring the relationship between cholesterol and synaptic function were included. When examining the relationship between lipids and synapses in various diseases, articles that focused solely on cholesterol in AD without also addressing synaptic dysfunction were excluded.

Lipid Classification and Function in the Nervous System

Lipids, a diverse group of water-insoluble organic compounds, encompass tens of thousands of known species. Within the nervous system, lipids can be broadly categorized into four classes: sterols (including cholesterol), glycerophospholipids, sphingolipids, and fatty acids (FAs).

FAs serve as the building blocks of complex lipid classes, except for sterols, which are characterized by a steroid backbone. FAs are carboxylic compounds consisting of hydrocarbon chains connected to a carboxyl group. On the basis of the number of carbon atoms in the chain, FAs are classified into short-chain FAs (≤ C5), medium-chain FAs (C6–12), and long-chain FAs (C13–21), and on the basis of the saturation of carbon-carbon bonds, they are classified into saturated FAs, monounsaturated FAs, and polyunsaturated FAs (PUFAs) (Bruce et al., 2017; Bogie et al., 2020; Figure 3A). FAs are the most abundant organic compounds in the brain, constituting 60% of its dry weight, with 20% being PUFAs. The brain’s most abundant PUFAs are omega-3 docosahexaenoic acid and omega-6 arachidonic acid (Zhou et al., 2022). Proper brain function relies on the availability of sufficient omega-3 PUFA levels. Omega-3 PUFAs, primarily docosahexaenoic acid (DHA) and eicosapentaenoic acid, exhibit strong anti-inflammatory and inflammation-resolving properties, counteracting the pro-inflammatory effects of omega-6 PUFAs, which serve as precursors to pro-inflammatory mediators (Bruce et al., 2017). While some FAs can be synthesized de novo, essential FAs such as DHA must be transported into the brain from systemic circulation. This process is dynamic, with up to 8% of essential PUFAs undergoing active turnover daily (Bruce et al., 2017).

Figure 3.

Overview of major lipid classes in the nervous system and sphingolipid metabolism.

(A) FAs are classified based on their saturation levels, with saturated FAs containing no double bonds, monounsaturated FAs possessing one double bond, and polyunsaturated FAs containing multiple double bonds. Glycerolipids are formed by attaching FAs to a glycerol backbone, while glycerophospholipids include additional phosphate and head groups. Sphingolipids feature a sphingosine backbone linked to a fatty acid chain, and sterols are characterized by tetracyclic ring structures. (B) Ceramide synthesis initiates de novo from serine and palmitoyl-CoA. Ceramide serves as a precursor for the biosynthesis of other sphingolipids, including sphingosine and sphingosine-1-phosphate, which is eventually irreversibly degraded by S1P lyase. FA: Fatty acid; S1P: sphingosine-1-phosphate.

Phospholipids are the main components of the bilayer structures of cell membranes. The bilayer arrangement ensures stability by shielding the hydrophobic tails from water while exposing the hydrophilic phosphate heads to the aqueous environment (Lordan et al., 2017).

Glycerophospholipids, diglycerides with a phosphate group, feature various head groups attached to the phosphate through phosphodiester linkages (Ademowo et al., 2024). Common head groups include choline, ethanolamine, serine, inositol, or glycerol, forming phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylinositol (PI), and phosphatidylglycerol (PG), respectively. PC and PE are the most abundant phospholipids in animal tissues (Farooqui et al., 2000; Figure 3A). Phosphatidic acid (PA), a lipid second messenger, is produced through the hydrolysis of PC by phospholipase D (PLD) (Weiss et al., 1959). It plays a crucial role in transmitting and amplifying intracellular signals, as well as regulating various cellular processes, including cell proliferation, vesicle trafficking, cytoskeletal reorganization, and morphogenesis (Jang et al., 2012). Plasmalogens are another subclass of phospholipids characterized by the presence of a vinyl ether bond at the sn-1 position and an ester bond at the sn-2 position of a glycerol backbone. Plasmalogens are predominantly categorized into ethanolamine plasmalogens and choline plasmalogens (Su et al., 2019). Phospholipids are an indispensable part of the cell membrane, and their changes are most obvious in the synaptic regions, where cell membrane changes are the most abundant. Their unique FA compositions and dynamic regulation are critical for maintaining synaptic integrity and facilitating efficient neurotransmitter release (Dorninger et al., 2017).

Sphingolipids, with a backbone of sphingosine, include ceramide, sphingosine-1 phosphate (S1P), ceramide-1-phosphate, ganglioside, and sphingomyelin (SM). Ceramide serves as a precursor for more complex sphingolipids and is synthesized through multiple pathways, including de novo synthesis, the sphingomyelinase pathway, or the salvage pathway with S1P intermediates (Colombo and Farina, 2022). Interestingly, sphingolipids exert contrasting effects on cellular survival and death signaling, evidently in the concept of a sphingolipid rheostat, and have a significant impact on aging and neurodegenerative diseases (Lucaciu et al., 2020; Figure 3B). In addition, high levels of SM have been found in the white matter of the brain, where it serves as a primary component of the myelin membrane. This myelin insulation accelerates nerve signal transmission and enhances the efficiency of the nervous system (Xiang et al., 2021). Glycolipids are widely found in the lipid membranes of living cells. They are composed of glycosyl groups attached to lipid molecules and are classified into glycoglycerolipids and glycosphingolipids (GSLs; Yi et al., 2023). GSLs are linked by glycosidic bonds between hydrophilic glycosyl groups and hydrophobic ceramides and perform recognition functions, which give them key roles in cellular communication, adhesion, and signal transduction (Jin and Yang, 2023). The classification and functions of GSLs have been extensively described in numerous studies (van Eijk et al., 2020; Huang et al., 2024).

Sterols are synthesized via the mevalonate pathway, which relies on the activity of the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Nes, 2011; DeBose-Boyd and Ye, 2018). Their distribution varies between plants and animals, with phytosterols commonly found in plants and animals predominantly producing the C-27 sterol cholesterol. As a pervasive and indispensable constituent of cellular membranes, cholesterol plays a pivotal role in regulating membrane structure and fluidity (Song et al., 2021). Moreover, cholesterol acts as a precursor for oxysterols, hormones, steroids, and bile acids, playing a crucial role in sustaining numerous metabolic processes (Luo et al., 2020; Figure 3A). Astrocytes are the primary cells in the CNS that contain higher levels of cholesterol due to their role as net producers and distributors of cholesterol. Neurons, on the contrary, are major consumers of cholesterol, relying on astrocyte-produced cholesterol for their metabolic needs, including maintaining neurites and synaptic connections (Zhang and Liu, 2015). Cholesterol in the brain is closely related to learning and memory (Saher, 2023). Increased cholesterol levels in neurons can enhance endoplasmic reticulum stress, leading to hippocampal neuronal apoptosis, cognitive decline, and brain atrophy (Djelti et al., 2015). Furthermore, cholesterol imbalance contributes to hippocampal neuron degeneration (Koudinov and Koudinova, 2001). A previous study has demonstrated that hypercholesterolemia in animal models results in cognitive deficits and structural changes in hippocampal neurons (Engel et al., 2019).

Due to their extensive diversity in the CNS, lipids perform various functions, including serving as metabolic substrates, structural components of membranes, and signaling molecules (Tracey et al., 2018, 2021). In the following sections, we explore synaptic lipid composition, vesicle trafficking, and molecular signaling transmission to deepen our understanding of the regulation of synapses by lipid molecules and their specific roles.

Lipid Composition in Synapses

The structure and composition of presynaptic and postsynaptic membranes resemble those of typical animal cell membranes. The composition of synaptic membranes undergoes dynamic changes during neural development. In rats, the levels of cholesterol, sphingolipids, and raft-associated PE increase progressively over time, particularly within the first 60 days after birth (Tulodziecka et al., 2016). Furthermore, the levels of GSLs rise progressively during postnatal development (Ngamukote et al., 2007). Brain synaptic density and the protein composition of synapses change throughout the lifespan of mice (Bulovaite et al., 2022); therefore, lipid changes have been hypothesized to play a synergistic role in the homeostasis to maintain synaptic function. Lewis et al. (2017) determined the lipid composition of isolated synaptic bodies, synaptic membranes, and synaptic vesicles (SVs) by mass spectrometry. Specifically, they found that SVs are enriched in triacylglycerides and sphingolipids, while synaptic membranes are partially enriched in phospholipids (Lewis et al., 2017). For instance, lipids in presynaptic membranes, particularly negatively charged PS and phosphatidylinositol-4,5-bisphosphate (PI4,5P2), play crucial roles in various stages of the SV cycle (Martin, 2001; Wenk and De Camilli, 2004). The electrostatic charge of these lipids facilitates the coupling of presynaptic exo- and endocytosis. Takamori et al. performed a quantitative lipidomics analysis of mammalian SVs using electrospray ionization tandem mass spectrometry (ESI-MS/MS) (Takamori et al., 2006). Their findings were largely consistent with those of a previous study using thin-layer chromatography (Nagy et al., 1976; Deutsch and Kelly, 1981). Mammalian SVs are rich in cholesterol, PC, PE, PS, and SM, which account for 40 mol%, 17 mol%, 20 mol%, 6 mol%, and 3.6 mol%, respectively (Takamori et al., 2006). The comprehensive lipid composition of SVs has been thoroughly summarized in one review (Binotti et al., 2021). Generally, the lipid composition of different synaptic components is closely related to their functional role. However, various technical constraints hinder the establishment of a comprehensive profile of the complete synaptic plasma membrane lipidome using current biochemical methods. For instance, synaptosome preparations and the isolation of PSD plasma membrane involve non-ionic detergents, which can influence the extracted lipid content (Zhao et al., 2014; Tulodziecka et al., 2016).

Role of Cholesterol in Synapses

Cholesterol metabolism and synapses

Cholesterol is a steroid that constitutes approximately 2%–3% of the brain’s total weight and accounts for 20%–25% of the total cholesterol content (Shin et al., 2024). The majority of cholesterol is synthesized within the brain itself rather than being transported from the bloodstream (Victor et al., 2022). This may result from the inability of lipoprotein particles, which are responsible for intercellular transport of steroids and other lipids, to cross the blood–brain barrier (BBB; Zhang and Liu, 2015). Cholesterol biosynthesis involves a series of enzymatic reactions, named Kandutsch–Russell and Bloch pathways. Neurons mainly contain sterols of the so-called Kandutsch–Russell pathway, whereas astrocytes contain precursors of the Bloch pathway (Zhang and Liu, 2015). Cholesterol synthesis in neurons is particularly crucial during the early stages of development. Adult neurons essentially rely on astrocytes for cholesterol. The absence of cholesterol synthesis in neuronal precursor cells results in a reduction in brain size and perinatal lethality (Saito et al., 2009; Lee et al., 2022).

Synaptogenesis demands substantial cholesterol levels, relying on cholesterol synthesized by astrocytes and its transportation through apolipoprotein E (APOE). Cholesterol produced by astrocytes is exported across the cell membrane via ATP-binding cassette transporters. Once outside the cell, it combines with APOE in the extracellular space to form high-density lipoprotein-like particles (Hirsch-Reinshagen et al., 2004; Turri et al., 2022). Ultimately, neurons absorb APOE-containing lipoproteins via low-density lipoprotein receptor (LDLR) and LDLR-related protein 1 receptors (Wahrle et al., 2004; Figure 4).

Figure 4.

Lipid crosstalk between neurons and glial cells.

Cholesterol biosynthesis in astrocytes begins with acetyl-CoA as a substrate, which is converted to HMG-CoA by HMG-CoA synthase. After a series of enzymatic reactions, cholesterol is synthesized. Cholesterol is transported out of astrocytes via ABCA1 and then binds with APOE. In neurons, cholesterol is converted to 24-OHC by CYP46A1. Secreted 24-OHC is taken up by astrocytes, activating nuclear LXR and promoting the transcription of ABCA1 and ApoE. Excess cholesterol in astrocytes is esterified by ACAT1/SOAT1 and stored as CE in LDs. Additionally, toxic FAs generated by hyperactive neurons can be transferred to astrocytic LDs, where they are metabolized via mitochondrial beta-oxidation, providing additional energy for the brain. APOE4 mutations lead to impairment ability of cleaning LDs, and LDs eventually accumulates in astrocytes. Compounds such as CYP46A1 activators, FA inhibitors, LXR agonists, and statins can modulate lipid metabolism pathways and may serve as potential targets for disease treatment in the future. 24-OHC: 24-Hydroxycholesterol; ABCA1: ATP-binding cassette transporter A1; ACAT1: acyl-CoA: cholesterol acyltransferase 1; APOE: apolipoprotein E; CE: cholesteryl ester; CMS121: 4-[4-(cyclopentyloxy)-2-quinolinyl]-1,2-benzenediol; CYP46A1: cytochrome P450 family 46 subfamily A member 1; ER: endoplasmic reticulum; FA: fatty acid; HMG-CoA: 3-hydroxy-3-methylglutaryl-CoA; LD: lipid droplet; LDLR: low-density lipoprotein receptor; LRP1: low-density lipoprotein receptor-related protein 1; LXR: liver X receptor; miRNA: microRNA; p-SREBP-2: phosphorylated sterol regulatory element-binding protein 2; SCAP: SREBP cleavage-activating protein; SOAT1: sterol O-acyltransferase 1.

Cholesterol synthesis, transport, and clearance in the CNS are continuous processes affected by many enzymes and complexes. Abnormalities in any one of these links can substantially affect synaptic function. Reductions in sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) levels and resultant reductions in cholesterol synthesis can have detrimental effects on synaptic transmission, cognitive function, and neuronal membrane properties (Brown and Goldstein, 2009; Suzuki et al., 2013). The lower levels of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins observed in mice lacking SCAP highlight the critical role of cholesterol in mediating vesicle fusion with the presynaptic membrane (van Deijk et al., 2017). In addition, disruptions in cholesterol trafficking from glia to neurons are associated with reduced excitatory synapses and impaired synaptic plasticity (Karasinska et al., 2009). Interestingly, in specific circumstances, such as the presence of brain-derived neurotrophic factor (BDNF), endogenous cholesterol synthesis is partially restored in neurons (Numakawa et al., 2010). Cytochrome P450 cholesterol 24-hydroxylase (CYP46A1) maintains brain cholesterol homeostasis by converting cholesterol into 24-hydroxycholesterol (24-OHC) to eliminate cholesterol from the brain (Lund et al., 2003; Figure 4). Cholesterol reduction by CYP46A1 triggers dendritic outgrowth and increases dendritic protrusion (Moutinho et al., 2016). The study utilized a model in which an AAV vector carrying a CYP46A1-specific shRNA was injected into the hippocampus of adult mice to inhibit CYP46A1 gene expression. This led to a 2- to 2.5-fold increase in total hippocampal cholesterol levels. The resulting cholesterol accumulation caused structural changes, including neuronal apoptosis, cognitive impairment, and hippocampal atrophy (Djelti et al., 2015). These studies highlight the dynamic balance of cholesterol metabolism in the nervous system, indicating the effects of cholesterol deficiency on synaptic function and the key roles of excessive cholesterol in memory processes and synaptic plasticity (Pikuleva and Cartier, 2021).

Synaptic plasticity is the key to brain learning and memory, and cholesterol is constantly communicated between various cells in the brain. Therefore, we hypothesized that cholesterol metabolism in cells may dynamically affect learning and memory through synapses. Interestingly, drugs targeting the whole cholesterol cycle, such as CYP46A1 activators, liver X receptor (LXR) agonists, and statins, can partially alleviate the progression of neurodegenerative diseases, reinforcing the importance of regulating cholesterol homeostasis in the CNS (Xu et al., 2013; Kosowski et al., 2021; Lerner et al., 2022).

Cholesterol and the synaptic vesicle cycle

Lipids play important roles at sites of membrane formation. Since synapses primarily transmit neurotransmitters through vesicles, this process requires rapid and extensive membrane remodeling (Coupland et al., 2024). For example, changes in cholesterol levels in hippocampal synapses can affect the absolute number of vesicles at the synapse and their spontaneous fusion and recycling (Wasser et al., 2007). This mechanism involves two major aspects: first, cholesterol forms nano-domains with transmembrane and membrane-associated proteins during SV cycling. Additionally, cholesterol enhances the lipid packing density in the membrane by filling the gaps between phospholipids, thereby increasing membrane stiffness and mechanical strength through interactions with fatty acyl chains within the bilayer’s hydrophobic core (Bruckner et al., 2009). An alternative hypothesis pertains to the effect of cholesterol on membrane fusion and fission mechanics. Cholesterol has been implicated in reducing repulsive forces between membranes, thereby lowering the energy required for membrane fusion and fission processes (Aeffner et al., 2012). Biophysical investigations suggest that membrane deformation triggers the diffusion of cholesterol toward curved membranes, facilitating membrane stress relaxation and mitigating the elastic energy associated with curvature (Bruckner et al., 2009). This mechanism may operate within invaginated endocytic coated pits, potentially assisting vesicle splitting. Indeed, changes in cholesterol concentration affect the rate of SV release and exocytosis (Petrov et al., 2015; Zakyrjanova et al., 2020).

Vesicular cholesterol facilitates the clustering or confinement of SV proteins during recycling (Puchkov and Haucke, 2013). Cholesterol influences both SV exocytosis and endocytosis by affecting membrane composition and lipid-raft domain organization (Lv et al., 2008; Giniatullin et al., 2024). Cholesterol-rich domains also recruit PI4,5P2 and promote actin polymerization, which plays an essential role in protein clustering. Disruption of actin, which serves as a scaffold in the actin-rich periactive zone, impairs SV endocytosis (Bloom et al., 2003). A previous study using the Drosophila shibire-ts1 (shi) mutant demonstrates that cholesterol extraction disrupts SV protein clustering, decreases presynaptic PI4,5P2 levels, and alters presynaptic actin organization, implicating vesicular cholesterol in the regulation of actin polymerization (Delgado et al., 2000). Inhibition of actin polymerization in this mutant leads to SV protein dispersal, impaired endocytosis, and reduced synaptic recovery after exocytosis. These findings indicate that vesicular cholesterol is essential for maintaining the confinement of SV proteins, which is mediated by actin, during recycling. Thus, alterations of membrane or SV lipids may affect the ability of synapses to undergo sustained synaptic transmission by compromising the recycling of SV proteins (Dason et al., 2014).

The PARK7 gene, which encodes the DJ-1 protein, is a multifunctional antioxidant stress protein. It plays a key role in cellular protection, molecular chaperoning, transcriptional regulation, and the maintenance of mitochondrial function. Mutations in this gene are closely associated with PD (Kalia and Lang, 2015). SV endocytosis is substantially impaired in DJ-1 knockout (KO) neurons. Re-expression of DJ-1 in neurons fully rescues these defects, whereas pathogenic DJ-1 mutants, such as L166P, fail to restore SV endocytosis. The depletion of cholesterol in neurons has been shown to mimic the SV endocytosis defects observed in DJ-1 KO neurons, while cholesterol supplementation has been suggested to restore the abnormal SV endocytosis function in DJ-1 KO neurons (Kyung et al., 2018). These findings suggest that DJ-1 regulates SV endocytosis by modulating cholesterol levels and fluidity in the synaptic membrane. However, the exact mechanism by which cholesterol regulates SV endocytosis remains unclear and requires further investigation. Cholest-4-en-3-one, oxime (olesoxime or TRO19622) is a cholesterol derivative considered as a promising therapeutic agent for neurodegenerative disorders (Weber et al., 2019). Olesoxime was found to restrict neurotransmitter release and SV translocation in mammalian neuromuscular junctions. The voltage-dependent anion channels in the plasma membrane are located in cholesterol-rich microdomains, where they negatively regulate neurotransmission by enhancing Cl^– transport, with olesoxime being a key modulator of this mechanism (Zakyrjanova et al., 2020). In summary, these findings indicate that cholesterol performs dual roles: promoting binding with SV-associated proteins and altering membrane dynamics during SV cycling, consistent with its high abundance in SV membranes (Figure 1).

Role of Phospholipids in Synapses

Phospholipids regulate multiple steps of the SV cycle and vesicle fusion. Phosphoinositides undergo reversible phosphorylation at specific hydroxyl (OH) positions of the myo-inositol ring, generating various isoforms with distinct cellular functions (PI3P; PI4P; PI5P; PI3,5P2; PI4,5P2; PI3,4P2; and PI3,4,5P3) (Preische et al., 2019). Among phosphoinositide species, PI4,5P2 is the most abundant at the plasma membrane, regulating membrane-trafficking events, particularly those related to plasma membrane dynamics. Neuronal exocytosis requires plasma membrane PI4,5P2, which serves as a molecular “beacon” guiding SVs to fusion sites. Levels of PI4,5P2 at the plasma membrane regulate vesicle-priming rates, the size of the readily releasable pool, and the rates of continuous exocytosis (Micheva et al., 2001; Wen et al., 2011). This regulation involves interactions between PI4,5P2 and proteins engaged in docking and fusion, such as rabphilin, synaptotagmin 1, SCAMP2, and Mints.

The most heavily studied members of the PI kinase family are the phosphoinositide 3-kinases (PI3Ks), which catalyze phosphorylation of the 3′ inositol ring to generate PI3P (Burke et al., 2023). At least in the early stages of synaptogenesis, PI3P is important for the collybistin-mediated recruitment of gephyrin and γ-aminobutyric acid (GABA) receptors to developing inhibitory post-synapses (Papadopoulos et al., 2017). Furthermore, neurotransmitter release and vesicle recycling are regulated by an intrinsic pathway involving the endosomal lipid PI3P. The VPS34-Cdk5 pathway modulates neurotransmission strength and vesicle-recycling efficiency by regulating PI3P synthesis, thereby maintaining appropriate neuronal excitability and preventing excessive excitation and epileptic-like activity (Liu et al., 2022). PI3K potentially plays distinct roles in different types of synaptic plasticity. In the hippocampus, PI3K is involved in the induction, maintenance, and expression of LTP, which is dependent on either N-methyl-d-aspartic acid (NMDA) receptor or group I metabotropic glutamate receptor 1 (mGluR1) (Sanna et al., 2002; Horwood et al., 2006). It also mediates various forms of long-term depression (LTD), such as mGluR1-induced LTD involving the PI3K-Akt-mTOR signaling pathway and orexin-induced LTD via GPCR, and PI3K activation (Daw et al., 2002; Hou and Klann, 2004; van der Heide et al., 2005). In the amygdala, PI3K is activated following tetanic stimulation in the cortico-lateral amygdala, contributing to LTP induction, and is crucial for fear conditioning and fear memory consolidation (Lin et al., 2001). The different roles of these processes in synaptic plasticity indicate the subtype-specific functions of PI3K, since different PI3K subtypes exhibit distinct signaling pathways, physiological functions, and brain distributions (Kim et al., 2011b).

PS, a predominant anionic phospholipid class, is notably abundant in the inner leaflet of the plasma membrane within neural tissues (Roots and Johnston, 1965). PS is transported via secretory vesicles from the Golgi to the plasma membrane, where it localizes exclusively within the cytoplasmic leaflet of the bilayer. Under high-frequency stimulation, the vesicle transport-related adaptor protein AP-3 transports the phospholipid flippase ATP8A1 to the axon. ATP8A1 then acts on PS, causing it to flip from the inner membrane to the cytoplasmic face of SVs. Subsequently, PS recruits synapsin1, which regulates the mobilization of SVs in the reserve pool and release pool, allowing for specific responses to high-frequency stimuli and the control of neurotransmitter release (Xu et al., 2023).

In conclusion, phospholipids are essential for the structure and function of SVs. By participating in exocytosis and recycling, they regulate neurotransmitter release and maintain synaptic membrane integrity (Figure 1). Furthermore, recent studies have highlighted the role of PS in activating key signal transduction pathways and regulating receptor function, renewing interest in its correlation with brain function.

Role of Sphingolipids in Synapses

Ceramides are generated through the breakdown of SM, a process facilitated by various sphingomyelinases, such as neutral sphingomyelinase 2 (nSMase2). nSMase found in the hippocampus influences postsynaptic function by modulating excitatory currents and NMDA receptor clustering (Dotti et al., 2014). nSMase increases the excitability of hippocampal neurons by enhancing action potential firing and reducing the slow after-hyperpolarization. This effect is mediated by the production of S1P from SM metabolism (Norman et al., 2010). SMase is also a significant factor in skeletal muscle atrophy. Its mechanism may involve hydrolysis of plasma membrane SM, which enhances the mobilization of SVs and facilitates the full fusion mode of exocytosis. However, this stimulatory effect can be reversed when the enzyme affects the membranes of SVs (Tsentsevitsky et al., 2023). Additional genetic and biochemical studies are required to characterize the precise molecular mechanisms of SMase-mediated changes in neuromuscular transmission and their contributions to skeletal muscle dysfunction and respiratory failure.

S1P regulates synapsin-I localization in presynaptic compartments and induces glutamate release, significantly influencing hippocampal glutamate transmission (Kanno et al., 2010; Riganti et al., 2016). Recent studies have suggested that sphingolipids’ involvement in synaptic function extends further (Vaughen et al., 2022), with the initial enzymatic process of sphingolipid production mediated by the influence of serine palmitoyltransferase subunit LACE/SPTLC2 on synaptic structure and function (West et al., 2018). Notably, the activity of basigin, an essential component of plasma membrane Ca²⁺-ATPases, may be affected by LACE mutations, potentially impacting Ca²⁺ dynamics at the synapse (Schmidt et al., 2017; West et al., 2018).

GSLs are abundant in the outer layer of neuronal plasma membranes and are involved in forming specialized areas such as synapses and axonal growth cones (Aureli et al., 2014). This specialization is crucial for synaptic function and neuronal communication. Gangliosides, sialic acid-containing GSLs, are crucial for synaptic plasticity, which underlies learning and memory. Studies on transgenic mice overexpressing β1,4 GalNAc-T, an enzyme that shifts gangliosides from the b-pathway (e.g., GQ1b, GT1b, GD1b) to the a-pathway, revealed significant effects on synaptic plasticity. These mice exhibited reduced LTP in hippocampal CA1 neurons, while LTD remained unaffected. Behaviorally, the mice showed impaired learning in the four-pellet taking test, despite showing no changes in general activity levels (Ikarashi et al., 2011). These findings highlight the critical role of b-pathway gangliosides in maintaining normal LTP and learning. GM1 ganglioside regulates synaptic function by modulating calcium signaling through interactions with synaptic proteins, particularly phosphorylated NMDA receptors. It enhances calcium flux, activates ERK signaling, and promotes synaptic spine formation (Weesner et al., 2024). Meanwhile, GSLs, as components of lipid rafts, play crucial roles in facilitating signal transduction within cellular membranes. Cara-Lynne Schengrund provided a more detailed description of the role of gangliosides in signal transduction (Schengrund, 2015).

These findings underscore the intricate link between sphingolipid metabolism and synaptic function, which influences synaptic transmission, neuronal survival, plasticity, membrane fusion, neurotransmitter release, and signal transduction (Figure 1). Moreover, dysregulation of sphingolipid pathways, particularly ceramide accumulation, may contribute to the neurodegenerative processes underlying conditions like AD (Haughey et al., 2010; Crivelli et al., 2020; Bouscary et al., 2021; D’Angiolini et al., 2022).

Role of Fatty Acids in Synapses

Very long-chain saturated FAs (VLC-SFAs) play critical roles in synaptic function by regulating SV fusion and synaptic plasticity. VLC-SFAs, which are enriched in SVs, influence the vesicle cycle by affecting membrane lipid composition, van der Waals interactions, and potentially interacting with proteins involved in vesicle docking, fusion, and endocytosis (Hopiavuori et al., 2018; Deák et al., 2019). Deficiency of VLC-SFAs, caused by mutations in ELOVL4 (e.g., W246G), leads to altered neurotransmitter release probability, changes in the readily releasable pool size, and reduced dendritic spine density in Purkinje cells, indicating both presynaptic and postsynaptic defects (Nagaraja et al., 2023). These impairments disrupt LTP/LTD, suppressing Purkinje cell output and contributing to motor incoordination and ataxia, as observed in spinocerebellar ataxia 34 models (Nagaraja et al., 2021).

Short-chain fatty acids (SCFAs), key metabolites derived from the gut microbiome, play a major role in synaptic plasticity, inflammation, and poststroke recovery by modulating microglial activity and immune responses (Park and Kim, 2021). Supplementation with SCFAs can improve exercise recovery, alter cortical connectivity, and increase the density of dendritic spines and synapses in excitatory neurons (Sadler et al., 2020). Transcriptomics analysis revealed that SCFAs primarily regulated genes associated with microglial activity, indicating an indirect effect on neuron plasticity through microglia. SCFAs reduce microglial activation, which enhances synaptic pruning and dendritic remodeling (Sadler et al., 2020). In addition, SCFAs regulate the inflammatory response by promoting the production of the anti-inflammatory cytokine IL-10 from T cells, macrophages, and microglia, which is crucial for their protective role in diseases such as experimental autoimmune encephalomyelitis (Smith et al., 2013; Sun et al., 2018). This dual role of SCFAs in modulating both synaptic plasticity and inflammation highlights their therapeutic potential in neurological diseases (Park and Kim, 2021).

FAs, especially omega-3 PUFAs, play an important role in synaptic function through various mechanisms. Omega-3 PUFAs, such as DHA, promote the growth of neurites and enhance neuronal differentiation. Deficiency of omega-3 PUFAs during development leads to shorter and fewer neurites in hippocampal neurons of rats and mice. DHA, through its metabolic product docosahexaenoyl ethanolamide, yields longer and more branched neurites. This is accompanied by increased synapsin expression, which supports synaptic maturation (Calderon and Kim, 2004; Kim et al., 2011a). DHA also interacts with GPCR-40 to promote neurogenesis in adults and increases hippocampal neuron size when combined with α-linolenic acid (Ahmad et al., 2002). Omega-3 PUFAs regulate vesicle recruitment, exocytosis, and neurotransmitter release. They enhance vesicle density in hippocampal terminals and influence glutamate loading by modulating vesicular transporters (Yoshida et al., 1997; Latour et al., 2013). DHA-enriched neurons exhibit heightened glutamatergic synaptic activity. Furthermore, omega-3 PUFAs regulate the SNARE complex assembly through interactions with syntaxin 3 and other proteins, which is critical for neurotransmitter release (Figure 1; Pongrac et al., 2007).

Omega-3 PUFAs enhance synaptic plasticity, which is vital for learning and memory. Deficiency in omega-3 PUFAs impairs LTP and reduces NMDA and AMPA receptor subunit expression, while supplementation improves LTP and counters age-related declines in plasticity (Kavraal et al., 2012). The combined effects of DHA consumption and physical exercise enhance learning abilities in rodents, as demonstrated in the Morris water maze test. This combination also promotes the production of key proteins, including syntaxin 3, Gap 43, CaMKII, BDNF, and synapsin. These proteins play key roles in the signaling pathways of neuronal development and synaptic plasticity (Wu et al., 2008; Chytrova et al., 2010). DHA modulates glutamate transport via GLAST and GLT-1 transporters and regulates astrocytic signaling pathways involving CaMKII and protein kinases (Grintal et al., 2009). Additionally, DHA promotes the coupling of astrocytes through connection protein 43, supporting their role in neuronal protection and homeostasis. Deficiency in omega-3 PUFAs exacerbates age-related dysfunction in astrocytes (Latour et al., 2013). In summary, omega-3 PUFAs are crucial for synaptic efficiency, plasticity and neuroprotection. They act on neurons, astrocytes, and synaptic components to optimize brain function.

Lipid Rafts as Signaling Platforms in Synaptic Signaling

The cellular membrane is conventionally depicted as a dynamic mosaic structure consisting of a fluid lipid bilayer interspersed with mobile proteins. This architecture provides a scaffold for orchestrating complex interactions among various molecules, necessitating precise temporal and spatial coordination (Viljetić et al., 2024). Among these components, lipid rafts emerge as pivotal platforms for organizing transmembrane and synaptic proteins, notably diverse protein kinases, kinase receptors, G proteins, and other signaling molecules crucial for synaptic signaling, plasticity, and maintenance. The evolution of the lipid-raft concept for sub-compartmentalization in cell membranes has been described by Lingwood and Simons. (2010). Cholesterol acts as an organizer of presynaptic lipid rafts within the active zone and serves as an essential structural component of the active zone (Korinek et al., 2020). Alterations in cholesterol can profoundly influence interactions between synaptic proteins and signaling molecules. These insights hold substantial implications for deciphering the intricacies of cellular signaling mechanisms and developing therapeutic interventions for associated diseases.

Cholesterol and synaptic ionotropic receptors

Cholesterol depletion is currently the most common method used to intervene in lipid rafts. By reducing cholesterol content, the stability of postsynaptic membrane lipid rafts can be altered, thereby affecting the function of synaptic receptors. Cells with depleted cholesterol show a reduction in the number of acetylcholine receptors (AChRs) present on their cell surface, possibly due to hindered transportation from the Golgi complex to the membrane and/or diminished membrane stability (Pediconi et al., 2004). This was demonstrated using a combination of biochemical, pharmacological, and fluorescence microscopy techniques to follow the fate of AChRs. Cholesterol can also be used as an endogenous regulator of synaptic receptor endocytosis. Disrupting cholesterol/sphingolipids of lipid rafts reduces the stability of surface AMPA receptors and leads to the loss of both inhibitory and excitatory synapses and dendritic spines, while also increasing the internalization of unstimulated receptors. This disruption can be induced by fumonisin B1 and mevastatin, inhibitors of sphingolipid and cholesterol synthesis, further highlighting the critical role of these lipids in maintaining synaptic stability (Hering et al., 2003). Meanwhile, cholesterol depletion alters the AChR internalization pathway, which requires the activity of Arf6 and its effectors Rac1 and PLD (Borroni and Barrantes, 2011). Additionally, lipid rafts significantly influence synaptic neurotransmission by affecting the size and quantity of postsynaptic NMDA and GABA receptor clusters (Hering et al., 2003). The results of a study on cultured hippocampal neurons indicated that altering cholesterol levels, whether by depletion or enrichment, reduced the efficacy of GABA at its receptor, indicating an optimal cholesterol level for maximal agonist potency (Sooksawate and Simmonds, 2001). These findings suggest that homeostatic control of cholesterol content may regulate the stability of cell surface organization and receptor domains (Table 1).

Table 1.

Receptors and mechanisms primarily affected by cholesterol changes on lipid rafts

Receptor	Change in cholesterol	Effect on receptors and mechanisms
GABA receptor	Increase/ Decrease	Decline in function (Sooksawate et al., 2001)
ACh receptor	Decrease	Impaired internalization (Pediconi et al., 2004)
		Decrease in number (Borroni et al., 2011)
AMPA receptor	Decrease	Impaired internalization (Hering et al., 2003)
5-HT1A receptor	Decrease	Altered internalization mechanisms (Kuma et al., 2020, 2021)
		Influence receptor diffusion (Pucadyil et al., 2004, 2005)
		Signaling impairment (Sarkar et al., 2023)
CB1	Increase	Decreased binding efficiency/Signaling impairment (Bari et al., 2005a)
	Decrease	Increased binding efficiency/Enhanced signaling (Bari et al., 2005b)

Lipid rafts are specialized membrane microdomains enriched in cholesterol and sphingolipids, playing a critical role in receptor localization, signaling, and function. Changes in cholesterol levels can alter receptor behavior, including internalization, diffusion, binding efficiency, and signaling pathways, which are crucial for understanding the pathophysiology of various neurological and systemic disorders. 5-HT1A: 5-Hydroxytryptamine 1A; AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; CB1: cannabinoid receptor 1; GABA: γ-aminobutyric acid; ACh: acetylcholine.

The depletion and oxidation of cholesterol produce different physiological effects, particularly concerning neurotransmission and synaptic function. Cholesterol depletion is typically achieved through methods such as ethyl-β-cyclodextrin or statin treatments. In comparison with the control group, these treatments reduce cholesterol in lipid rafts by 40%–50%, leading to significant changes in the structure and function of the synaptic membrane and causing an increase in the spontaneous release of neurotransmitters such as acetylcholine (Rodrigues et al., 2013). In contrast, low concentrations of cholesterol oxidase result in the oxidation of cholesterol on the plasmalemma, which enhances SV mobilization. However, the oxidation of cholesterol in the SV membrane decreases the involvement of these SVs in subsequent rounds of neurotransmitter release (Zakirjanova et al., 2023). These two treatment approaches may yield opposing effects in physiological and pathological states, reflecting the distinct roles of cholesterol and lipid rafts. Therefore, determining the state of cholesterol and its impact on synaptic transmission are essential when studying the functions and diseases of the nervous system.

Cholesterol and G-protein coupled receptors

GPCRs interact primarily with cholesterol and PIP phosphate lipids, which are the predominant lipid types involved (Sejdiu and Tieleman, 2020). While the surface of rhodopsin shows specific sites for interaction with phospholipids (affinity ranking as PE > PS > PC), the effect of cholesterol on GPCR activity has been better documented (Soubias et al., 2006; Khelashvili and Menon, 2022). Cholesterol modifies receptor-ligand binding and signaling by altering receptor conformation and affecting receptor mobility within the lipid bilayer, which is crucial for G-protein coupling. It also influences receptor trafficking events such as sequestration, internalization, and recycling.

The 5-hydroxytryptamine 1A (5-HT1A) receptors play a pivotal role in the GPCR family, affecting various neurological, behavioral, and cognitive functions (Tiwari et al., 2021). Widely used antidepressant medications act as selective serotonin reuptake inhibitors in a mechanism that involves endocytosis of the 5-HT1A receptors (Borroto-Escuela et al., 2021). Statins are drugs used to induce chronic cholesterol depletion by inhibiting HMG-CoA reductase, a key enzyme in cholesterol biosynthesis. Using quantitative flow cytometry and confocal microscopy, researchers demonstrated that this depletion caused a switch in the internalization mechanism of 5-HT1A receptors from clathrin-mediated to caveolin-mediated endocytosis. Furthermore, under these conditions, a substantial proportion of the internalized receptors were redirected from the endosomal recycling pathway to lysosomal degradation (Kumar and Chattopadhyay, 2020, 2021). Cholesterol plays a dual role in regulating 5-HT receptor function. It governs intracellular transport and diffusion and modulates signal-transduction pathways. For instance, cholesterol depletion disrupts lipid rafts, leading to reduced binding of antagonists to 5-HT1A receptors (Pucadyil and Chattopadhyay, 2004, 2005; Sarkar and Chattopadhyay, 2023; Table 1). Cholesterol also modulates the sensitivity of 5-HT1A receptors, influencing the brain serotonin system in the medial prefrontal cortex to reverse depressive-like behaviors induced by chronic stress (Sun et al., 2015). Beyond cholesterol, various lipid types exert diverse effects on 5-HT1A receptor activity. Kumar et al. (2021) demonstrated that inhibiting sphingolipid biosynthesis impaired the trafficking of 5-HT1A receptors to the plasma membrane without altering total receptor levels. This highlights the regulatory role of lipids not only in the endocytosis and trafficking of 5-HT1A receptors but also in modulating their function.

The endocannabinoid system consists of endogenous cannabinoids (eCBs), enzymes involved in their synthesis and metabolism, and cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) (Lu and Mackie, 2021). eCBs act as retrograde messengers, transiently or persistently suppressing neurotransmitter release in excitatory and inhibitory synapses (Chevaleyre et al., 2006; Alger, 2012; Katona and Freund, 2012). Additionally, the endocannabinoid system has been implicated in synapse formation and neurogenesis (Stachowicz, 2023). By modulating synaptic strength, eCBs regulate diverse neural functions such as motor control, feeding behaviors, cognition and pain perception.

CB1, the primary cannabinoid receptor in the nervous system, is one of the most abundantly expressed GPCRs in the CNS and is predominantly found in neurons (Hoffman et al., 2021). High densities of CB1 are located in axons, particularly at presynaptic terminals. CB1 plays a pivotal role in modulating neurotransmitter release in synapses involving glutamate and GABA, thereby maintaining a delicate balance between brain excitation and inhibition (den Boon et al., 2015). Studies conducted over the past decades have demonstrated that the cholesterol content in cell membranes and the integrity of lipid rafts significantly influence CB1 function (Bari et al., 2005b; Oddi et al., 2011). Cholesterol enrichment in cell membranes reduces CB1 binding efficiency and activation, potentially influencing its protective role against cannabinoid-induced apoptosis signaling pathways (Bari et al., 2005a). Conversely, acute cholesterol depletion enhances this signaling pathway in neurons (Bari et al., 2005b; Table 1). Moreover, cholesterol may increase the immobile fraction of CB1 by promoting its interaction with highly immobile proteins in the membrane (Oddi et al., 2011). Recent research suggests that cholesterol content in lipid bilayers influences CB2 activation and alters the pharmacological classification of its ligands, impacting G-protein recruitment (Yeliseev et al., 2021). In detail, cholesterol increases the constitutive activity of CB2, enhancing basal signaling and influencing the efficacy of synthetic and natural ligands by altering receptor-ligand interactions. This cholesterol-dependent regulation may explain tissue- and cell-specific differences in the pharmacological behavior of CB2 ligands (Yeliseev et al., 2021).

Furthermore, membrane cholesterol is crucial for ligand binding and intracellular signaling in various receptors, including subtype 2 galanin receptor, oxytocin receptor, and cholecystokinin receptor (Pang et al., 1999; Harikumar et al., 2005). Purine receptors, particularly the subtypes P2Y2, P2X7, and A2A, play critical roles in cellular signaling. Cholesterol levels modulate the sensitivity and function of P2X7 receptors through their impact on pore gating and receptor currents. Specifically, cholesterol depletion enhances the activity of P2X7 receptors. This modulation ultimately affects purine receptor-dependent neurotransmission (Murrell-Lagnado, 2017; Passarella et al., 2022). Additionally, cholesterol can directly interact with receptors, such as ion channels and neurotransmitter receptors, through specific binding sites, modulating receptor conformation, stability, and function, ultimately impacting synaptic transmission and neuronal activity.

Cholesterol derivatives such as 24-hydroxycholesterol and 5α-cholestan-3-one substantially modulate synaptic transmission at both presynaptic and postsynaptic levels. 24-Hydroxycholesterol enhances NMDA receptor function and SV cycling, while 5α-cholestan-3-one reduces neurotransmitter release (Paul et al., 2013; Sun et al., 2016; Kasimov et al., 2017). These effects are mediated through various mechanisms, including modulation of NO synthesis and lipid-raft stability (Kasimov et al., 2016). A recent study has underscored the broader significance of membrane lipids in regulating synaptic receptors, ion channel activity, action potential propagation, neuronal development, and functional plasticity (Incontro et al., 2025).

Lipid Molecules Regulate the Connections Between Glial Cells and Synapses

Astrocyte-neuron coupling in lipid metabolism

Astrocytes are pivotal players in central CNS synapses, forming a crucial component of the tripartite synapse. The ability of astrocytes to detect and respond to neuronal activity profoundly influences synaptic development and plasticity across developmental stages and adulthood (Baldwin et al., 2021; Chung et al., 2024). Astrocytes provide energy support to synapses, regulating energy production through diverse mechanisms to meet the high energy demands of neurons (Petit and Magistretti, 2016). High levels of FA are associated with cytotoxicity and metabolic disorders. Stimuli such as synaptic activity or depolarization can increase intracellular calcium levels in neurons, which activates enzymes such as phospholipase A2 (PLA2; Ke et al., 2020). PLA2 hydrolyzes membrane phospholipids to release FAs such as arachidonic acid and DHA. Astrocytes play key roles in the uptake and metabolism of FAs. This process is primarily receptor-mediated and involves specific transport proteins, such as FA transport proteins (Liu et al., 2017). In some cases, free FAs can diffuse across the astrocytic membrane, although this is less common than receptor-mediated mechanisms (Falomir-Lockhart et al., 2019; Figure 4). In contrast to neurons, astrocytes can efficiently metabolize FAs, and FA oxidation—predominantly in astrocytes—contributes ~20% of the total brain energy supply (Zhang et al., 2023, 2024b). Breakdown of FA by β-oxidation and storage of FA in intracellular lipid droplets (LDs) are two complementary pathways used to reduce the intracellular FA load and protect cells from lipotoxicity (Figure 4).

During intense neuronal activity or oxidative stress, neurons can prompt adjacent astrocytes to form LDs (Bailey et al., 2015; Liu et al., 2015). Ioannou et al. (2019) demonstrated that these LDs serve as reservoirs for the toxic FAs generated by hyperactive neurons, which are subsequently metabolized by astrocytes through mitochondrial β-oxidation, providing additional energy to cope with metabolic stress (Figure 4). Recent studies in AD models have revealed disruptions in lipid metabolism (Pennetta and Welte, 2018; Li et al., 2022), with APOE4 expression leading to the accumulation of LDs. This phenomenon results in reduced FA uptake and oxidation in isolated cultured astrocytes (Farmer et al., 2019). These findings are consistent with the results obtained using neuron-astrocyte co-culture systems, which show that APOE4 mutations lead to impairment of neuronal LD synthesis, neuron-to-astrocyte LD transport, and the ability of astrocytes to degrade FA. Eventually, the metabolic and synaptic support provided to neurons by astrocytes is diminished (Qi et al., 2021). In conclusion, astrocytes function as energy regulators that can respond to oxidative stress in neurons. Simultaneously, astrocyte-related lipid metabolism disorders induce lipotoxicity in neurons and hinder the normal physiological function of neurons. However, the relationship between astrocytes and lipid metabolism requires elucidation, especially the effect of abnormal lipid metabolism on astrocyte reactivity. Additionally, Li et al. (2024) identified accumulation of excessive unsaturated FAs within neurons affected by Tau protein pathology. This accumulation prompts neurons to offload surplus lipids onto microglia, leading to LD aggregation, inflammation, and compromised microglial function, exacerbating neuronal stress. Similarly, in a Leigh Syndrome mouse model, neuronal mitochondrial abnormalities have been shown to result in glial LD accumulation (Liu et al., 2015). Although these findings suggested a potential link between LD accumulation and neurodegeneration, the existing studies have not clarified whether LD accumulation acts as a driver or a consequence of neurodegenerative processes.

Astrocytes wield influence over neurons not only through lipid energy metabolism but also by orchestrating synaptic structure and function through a variety of lipid molecules, with cholesterol being paramount. Particularly, cholesterol derived from astrocytes plays a pivotal role in synaptic function. Additionally, PA, another lipid derived from astrocytes, has been found to regulate neuronal neurite growth and dendritic branching. This was demonstrated through the targeted inhibition of PLD1, the enzyme responsible for PA production in astrocytes. PLD1 inhibition led to a marked reduction in PA secretion, resulting in a significant decrease in neurite dendritic branching (Zhu et al., 2016). PA also serves a critical role in vesicle fusion processes (Raben and Barber, 2017). Enzymes controlling PA production are believed to be primary regulators of the SV cycle (Puchkov and Haucke, 2013; Barber et al., 2018). Lipid molecules play diverse roles in the interactions between neurons and astrocytes. These interactions include responding to oxidative stress of neurons and supporting synaptic structure and function.

Lipids in oligodendrocytes and synapses

Oligodendrocytes, a type of neuroglial cells in the CNS, play a crucial role in myelin production. While most biological membranes contain similar amounts of proteins and lipids, myelin stands out with high lipid content (70%–85%), which is primarily composed of cholesterol, phospholipids, and glycolipids (Poitelon et al., 2020; Barnes-Vélez et al., 2023; Xu et al., 2024; Table 2). These lipids are essential for various aspects of myelin function, including axonal myelin assembly, structure, and neuronal signaling. While myelin has been traditionally considered to be highly stable and metabolically inert, myelin maintenance is now understood to be a dynamic and active process. For example, disruption of the cholesterol biosynthetic pathway mediated by SREBP2 can result in blunted myelin formation and lead to severe congenital myelin developmental disorders, accompanied by motor deficits and high disease prevalence (Zhou et al., 2021). Two key glycolipids in the myelin membrane, galactosylceramides and galactosulfatides, are essential for myelin structure and long-term stability (O’Brien and Rouser, 1964). Galactosylceramides, which are highly hydrophobic molecules, work with hydrophobic myelin proteins to generate intermolecular hydrophobic forces. These forces facilitate myelin membrane “zippering,” bringing membranes into close contact while repelling extracellular and cytosolic fluids (Bakhti et al., 2014). Disorders of glycosphingolipid metabolism, such as metachromatic leukodystrophy, Krabbe disease, and type A Niemann-Pick disease, can lead to lipid accumulation, cytotoxicity, and demyelination (Polten et al., 1991; Geberhiwot et al., 2023).

Table 2.

Main lipid compositions of myelin

Lipid class	Barnes-Vélez et al., 2023	Xu et al., 2024	Chrast et al., 2011
Cholesterol	46%	27%	26%
Glycolipid	20%	31%	31%
Galactosylceramide	17%	22%	14%–26%
Phospholipids	26%	40%	33%
Sphingomyelin	6%	6%	3%

The values of the primary myelin lipids are inferred from data provided by Barnes-Vélez et al. (2023), Xu et al. (2024), and Chrast et al. (2011), and are expressed as mol percent.

Recent research has revealed a close relationship between neuronal activity and myelination. Neuronal activity regulates the proliferation and differentiation of oligodendrocytes in vivo, promoting myelin formation. This activity-dependent myelination is associated with enhanced behavioral function in mice (Gibson et al., 2014). In zebrafish models, SV release influences the number of myelin sheaths in oligodendrocytes. Disrupting SV release leads to a notable reduction in myelin sheaths while stimulating neurons promotes myelin sheath production in an activity-dependent manner based on SV release (Mensch et al., 2015). Korrell et al. (2019) suppressed vesicle release by specifically targeting the SNARE protein SNAP-25 in oligodendrocyte precursor cells; this approach resulted in decreased levels of MBP protein and a reduction in the number of myelin sheaths projecting into the cortex. Moreover, evidence suggests that axonal vesicle fusion and myelin formation mutually reinforce each other. Vesicle fusion intensifies with myelination, concentrating at hotspots on the heminode, the non-myelinated domain where myelin sheaths extend (Almeida et al., 2021; Figure 5). Thus, vesicle fusion orchestrates myelin formation, with myelin presence acting as a positive feedback signal for further vesicle fusion and myelin growth. This mechanism may elucidate how enhanced oligodendrocyte myelination can mitigate synaptic loss and foster functional recovery in the chronic hypoxia model in neonatal mice (Wang et al., 2018). This intricate interplay between myelin sheaths and neuronal synapses highlights the complexity of neural communication.

Figure 5.

Relationship between lipids and synaptic interactions involving microglia and oligodendrocytes.

Oligodendrocytes wrap around neuronal axons to form myelin sheaths, with synaptic vesicle release and fusion influencing the number of myelin sheaths. This relationship is reciprocal: myelin sheaths can positively affect synaptic vesicles, and vice versa. Microglia express various receptors, including TREM2, CR3, and GPR56, which bind to PS. Additionally, S1P can bind to TREM2, potentially acting as a signaling molecule to induce microglial phagocytosis. Microglia play a critical role in clearing myelin debris; however, impaired cholesterol metabolism—due to factors such as TREM2 deficiency or aging—leads to lipid accumulation. This abnormal lipid metabolism disrupts microglial function, creating a vicious cycle that exacerbates demyelination. Under these conditions, cholesterol efflux, which relies on ABCA1 and LXR signaling, becomes insufficient. Stimulation by myelin debris further drives the accumulation of neutral lipids (e.g., cholesteryl esters and triglycerides) in microglia, overwhelming their lipid degradation systems and hindering recovery in white matter. ABCA1: ATP-binding cassette transporter A1; C1q: complement component 1q; C3: complement component 3; CR3: complement receptor 3; GPR56: G protein-coupled receptor 56; LD: lipid droplet; LXR: liver X receptor; PS: phosphatidylserine; S1P: sphingosine-1-phosphate; S1PR: sphingosine-1-phosphate receptor; SV: synaptic vesicle; TREM2: triggering receptor expressed on myeloid cells 2.

Synaptic damage coexists with myelin instability in AD. Two observations related to myelin sheath are worth noting. First, AD is associated with significant disruption in brain lipid metabolism, particularly in the abundant lipids in the myelin sheath. Second, instability in the myelin sheath contributes to the progression of AD. Magnetic resonance imaging studies on healthy control group and AD patients showed an accelerated decline in white matter integrity in AD patients compared to age-matched control group, which is also associated with the pathological staging of AD (Bartzokis et al., 2003; Kantarci et al., 2017). Additionally, decreased cerebral sulfatide levels have been observed in postmortem brain tissue in early AD. Loss of myelin and memory deficits are closely linked to aging and precede amyloid and tau pathology in AD development (Ates et al., 2020). Myelin dysfunction can cause abnormal aggregation of amyloid plaques and increase amyloid precursor protein (APP) cleavage in the cortex. Additionally, amyloid-β (Aβ) peptides can activate the nSMase-ceramide cascade through oxidative mechanisms, leading to oligodendrocyte death (Lee et al., 2004). The correlation between lipid imbalance and demyelination remains largely unexplored and is worth further investigation. Such studies can enhance our understanding of lipid-dependent myelin homeostasis and reveal new therapeutic approaches for disease-related demyelination (Berghoff et al., 2022; Barnes-Vélez et al., 2023).

Lipid and microglial phagocytosis

The intricate development of a well-connected nervous system encompasses regulation of synapse formation, controlled removal of surplus synapses, and maintenance of appropriate connections. Microglia, the resident macrophages of the CNS, occupy the entire CNS parenchyma and play a crucial role in eliminating excessive synapses (Ferro et al., 2018). The mechanisms undergoing microglial synaptic pruning and its involvement in diseases have been extensively investigated (Wu et al., 2015; Edmonson et al., 2016; Druart and Le Magueresse, 2019; Bartels et al., 2020; Li et al., 2020; Tuan et al., 2021). Notably, several receptors, including microglial complement component 1q (C1q) receptor (CR3) and the triggering receptor expressed on myeloid cells 2 (TREM2), are key players in this process (Zhong et al., 2023).

Microglia utilize various lipid mediators to exert their phagocytic function. Among these lipids, PS serves as a well-known “eat-me” signal. PS exposure on injured axons or dendrites marks them for elimination while sparing uninjured cell structures. Microglia recognize exposed PS through TREM2, leading to the engulfment of apoptotic cells (Maruoka and Suzuki, 2021; Nagata and Segawa, 2021). A recent study utilizing super-resolution microscopy techniques, co-cultured three-dimensional (3D) live imaging, and in vivo lipid imaging in genetic models, has elucidated how microglia target and remove PS-exposed synapses, particularly under conditions of Aβ oligomer stimulation. In detail, microglia target and remove these externalized PS-positive synapses via TREM2 to improve Aβ-induced synaptic hyperactivity (Rueda-Carrasco et al., 2023). Additionally, GPR56 expressed in microglia interacts with PS and facilitates the engulfment of PS-positive synapses. Similarly to C1q, the absence of microglial GPR56 results in an increase in synapses and a decrease in microglial engulfment of presynaptic inputs in the developing dLGN (Li et al., 2020; Scott-Hewitt et al., 2020; Figure 5).

Furthermore, S1P, a critical sphingolipid metabolite, has emerged as a regulator of microglial phagocytosis. S1P acts through its receptors (S1PR1–5), including S1PR1 expressed on neurons, in both autocrine and paracrine manners that promote neuronal development and axon outgrowth (Xue et al., 2022). In addition, TREM2 has been found to have a potential targeted interaction with S1P, a key lipid molecule in the sphingolipid signaling pathway, indicating that the sphingolipid pathway may be involved in TREM2-regulated microglial synaptic phagocytosis (Xue et al., 2022; Figure 5). This provides a new target for the development of drugs to intervene in synaptic damage.

Complement proteins such as C1q are expressed in neurons postnatally after interactions with immature astrocytes and are localized at the synapses (Scott-Hewitt et al., 2024). C1q is likely involved in synaptic phagocytosis and cleanup, facilitating the identification of synapses by microglia, the sole cells in the brain capable of expressing CR3 (Presumey et al., 2017; Shah et al., 2021; Chung et al., 2023). During pathological states, C1q interacts with the presynaptic membrane during PS exposure, promoting microglial engulfment (Scott-Hewitt et al., 2020; Figure 5). In humans, the levels of complement factors C3 and C4 have been associated with cardiometabolic risk factors such as obesity, insulin resistance, fat distribution, metabolic syndrome, and diabetes (Arias de la Rosa et al., 2020; Copenhaver et al., 2020; Fu et al., 2020). Similarly, alterations in lipid metabolism, particularly related to omega-3 FAs, have been linked to changes in complement cascade protein expression in microglia and exacerbated spine phagocytosis (Madore et al., 2020). In animal models, consumption of a high-fat diet (HFD) in the short term triggered a minor increment in both C1q and C3, along with a reduction in CD47 on synapses of aged mice, with a general trend hinting that a HFD alters these immunological indicators and enhances phagocytosis of synapses (Butler et al., 2023).

Abnormal lipid metabolism in microglia

Both mouse and human brains exhibit a notable accumulation of LDs in microglia with age. These cells exhibit increased production of reactive oxygen species, secrete pro-inflammatory cytokines, and display impaired phagocytic activity, a condition referred to as LD-accumulating microglia (Yousef et al., 2019; Marschallinger et al., 2020a). Studies have revealed that in the aged hippocampus, more than half of the microglia are in the LD-accumulating microglia state (Marschallinger et al., 2020b; Cheng et al., 2025). Interestingly, inhibiting LD formation has been shown to enhance the phagocytic activity of BV2 cells, indicating that LDs have a negative impact on phagocytosis, possibly due to their effect on microglial lysosomes (Filipello et al., 2023). In addition, drugs that interfere with microglial lipid metabolism have been shown to ameliorate synaptic loss in mice in AD models (Litvinchuk et al., 2024). TREM2 is a crucial transcriptional regulator of lipid transport and metabolism in microglia (Li et al., 2022). Loss of TREM2 function affects the clearance of myelin debris in demyelinated areas without affecting the number of microglia (Cignarella et al., 2020; Wang et al., 2023). This may be related to cholesterol esterification and LD-formation disorders in microglia after TREM2 deletion (Nugent et al., 2020; Figure 5). Disturbance of cholesterol metabolism caused by TREM2 deficiency inhibits demyelination and remyelination, underscoring the intricate relationship between lipids, microglia, and phagocytosis. Chronic HFD consumption leads to significant alterations in microglial lipid metabolism and synaptic function. Microglia in HFD-fed mice exhibit an activated phenotype, which is characterized by reduced territory area, increased CD68 immunoreactivity, and enhanced engulfment of postsynaptic density 95 puncta. Histological analysis reveals an accumulation of LDs in the microglia and hippocampal regions (Zhuang et al., 2022). Microglia containing LDs are generally believed to represent a primary harmful microglial state in the aging brain. Cellular LD accumulation could either be a cause or a consequence of cellular dysfunction, such as enhanced lipid phagocytosis or impaired enzymatic degradation and lipid phagocytosis (Marschallinger et al., 2020b; Filipello et al., 2023). Therefore, dietary lipids may play a driving role in the buildup of LDs in microglia, alongside aging, thereby exacerbating pathological processes that could lead to neurodegenerative disorders.

Myelin is composed of various lipids, and its integrity is compromised in neuromyelitis optica spectrum disorder (NMOSD), which is an inflammatory demyelinating disease. Clinical studies have shown that in comparison with the control group, NMOSD patients have elevated serum low-density LDL, triglycerides, and neurofilament light chain levels (Niiranen et al., 2021; Scott-Hewitt et al., 2024). A strong positive correlation between serum LDL levels and both expanded disability status scale scores and neurofilament light chain levels suggests that LDL contributes to NMOSD disease activity and progression. In NMOSD, a leaky BBB allows LDL to enter the brain parenchyma and accumulate in demyelinating lesions (Scott-Hewitt et al., 2024). Once inside the CNS, LDL is phagocytosed by microglia, leading to their activation. This activation is associated with metabolic reprogramming, including increased glycolysis and impaired cholesterol efflux, which exacerbates demyelination (Apaijai et al., 2019). LDL-treated microglia accumulate excessive myelin debris and lipid droplets. Although debris removal can support myelin regeneration, excessive accumulation causes microglial dysfunction, impairs debris degradation, and promotes the production of pro-inflammatory cytokines (Zhou et al., 2023). Co-culture experiments have demonstrated that LDL-treated microglia inhibit the maturation of oligodendrocyte precursor cells, further impairing myelin regeneration. In chronic cerebral hypoperfusion (e.g., white matter ischemic injury), plasma LDL leaks into brain tissue through the damaged BBB. Vessel-adjacent microglia are specifically activated by LDL and myelin debris, initiating pathological processes. LDL and myelin stimulation lead to the accumulation of neutral lipid species, such as cholesteryl esters and triglycerides, in microglia (Zhou et al., 2024). This excessive lipid burden overwhelms the cellular lipid degradation systems, accelerating demyelination and hindering white matter recovery. One study showed that knocking down LDLR in microglia or lowering circulating LDL levels can protect white matter and reduce ischemic demyelination (Zhou et al., 2024). LDL interventions may indeed regulate the morphology and lipid metabolism of microglia, alleviate lipid overload, and restore their reparative function. In addition, microglia promote the repair of demyelinated lesions through post-squalene sterol synthesis (Berghoff et al., 2021b). By integrating expression profiling, genetics, and comprehensive phenotyping, as well as in vitro and in vivo experiments, instead of producing cholesterol, microglia synthesize desmosterol, a cholesterol precursor, which activates LXR signaling to resolve inflammation and create a permissive environment for oligodendrocyte differentiation and remyelination (Berghoff et al., 2021b). Squalene supplementation enhances this process by increasing desmosterol levels, boosting LXR target gene expression, and facilitating cholesterol efflux from lipid-laden microglia (Gylling and Miettinen, 1994; Berghoff et al., 2021b; Figure 5). This reduces inflammation, promotes oligodendrocyte differentiation, and enhances myelin repair. These findings highlight the critical role of post-squalene sterol synthesis in microglia for resolving inflammation and repairing demyelinated lesions.

Lipoxygenases (LOXs) are a group of iron-containing, non-heme enzymes responsible for producing lipid mediators that influence cellular inflammation by oxidizing PUFAs (Chen and Zou, 2022). Many studies have highlighted the critical involvement of the LOX pathway, particularly the 5-LOX and 12/15-LOX pathways, in regulating neuroinflammation mediated by microglia (Zhao et al., 2020; Cheng et al., 2021). The 5-LOX and 12/15-LOX pathways regulate synaptic pruning and phagocytosis by microglia, affecting neurodevelopment. For the 5-LOX pathway, Barbosa-Silva et al. demonstrated that 5-LOX-deficient mice (5-LOX^–/–) exhibit increased synaptic density in brain regions such as the motor cortex and hippocampus, possibly due to reduced microglial synaptic pruning (Barbosa-Silva et al., 2022). This was associated with upregulated CX3CR1 and decreased CX3CL1 levels, despite no observed changes in microglia morphology or complement gene expression. The decreased pruning resulted in motor deficits and more repetitive behaviors. The 12/15-LOX pathway, on the contrary, is activated in microglia when the maternal diet is deficient in omega-3 PUFAs, leading to an overproduction of omega-6 PUFA derivatives such as 12-HETE. This dysregulates microglial homeostasis and enhances synaptic phagocytosis, driven via the complement cascade system (Madore et al., 2020). These changes disrupt synaptic remodeling, causing hippocampal network dysfunction and cognitive impairments, including spatial memory deficits, in offspring mice.

In summary, lipids influence microglial phagocytosis through two primary mechanisms. First, lipid molecules can act as ligands of receptors on microglia, inducing specific synaptic phagocytosis and affecting synaptic function. Second, lipid metabolism disorders within microglia themselves can impair their chemotaxis and phagocytosis, possibly due to dysfunction in the endoplasmic reticulum and lysosomes (Victor et al., 2022; Filipello et al., 2023). Understanding these intricate interactions is essential for elucidating the pathophysiology of neurodegenerative diseases and developing targeted therapeutic strategies.

Regulation of Synapses by Lipids: Implications for Diseases

Alzheimer’s disease

AD is a progressive neurodegenerative disorder characterized by memory loss and behavioral changes (Frisoni et al., 2022; Gustavsson et al., 2023). It involves the loss of synapses and neurons, alongside the accumulation of extracellular Aβ plaques and intracellular neurofibrillary tangles. The risk factors for AD are closely linked to lipid metabolism. These factors include genetic risks identified through genome-wide association studies and lifestyle risks identified from epidemiological research (El Gaamouch et al., 2016; Wu et al., 2024). Among the leading genetic risk factors for sporadic late-onset AD are APOE, APOJ, PICALM, ABCA7, TREM2, and ABCA1, all of which are directly involved in lipid trafficking, synthesis, and signaling. Additionally, SREBP-2, a key regulator of cholesterol metabolism, is genetically associated with variations in AD risk (Yin, 2023). Clinically, lipidomics and metabolomics studies have consistently shown changes in the levels of various lipid classes in the brain in the early stages of AD (Kao et al., 2020; Li et al., 2023). The majority of these were sphingolipids and glycerophospholipids, with sphingolipid levels being elevated and glycerophospholipid levels reduced (Varma et al., 2018). AD severity is associated with the levels of lipid metabolites, especially triglycerides and sphingolipids, which were identified as high-performance markers to distinguish AD from controls (Nie et al., 2024). Mechanistic studies conducted over the past decades have revealed multifaceted interactions between lipid metabolism and key pathogenesis mechanisms of AD, including amyloid degeneration, bioenergetic defects, oxidative stress, and neuroinflammation (Papotti et al., 2022).

Aβ peptides are derived from APP through cleavages mediated by β-secretase and the γ-secretase complex (Kapadia et al., 2024). This process is thought to occur within lipid rafts rich in cholesterol and sphingolipids. Therefore, cholesterol and sphingolipids influence amyloidosis. Chronic γ-secretase inhibition specifically reduces cholesterol levels in neurons, leading to decreased presynaptic neurotransmitter release probability and impaired synaptic transmission, despite an increase in synapse numbers. This reduction in cholesterol levels also upregulates neuron-specific cholesterol-synthesis genes, highlighting cholesterol metabolism as a key pathway linking γ-secretase activity to synaptic function and AD pathology (Essayan-Perez and Südhof, 2023). Aβ production is influenced by cholesterol levels in neuronal membranes. Increased membrane levels of cholesterol, as observed in sporadic AD, can trigger elevated production of Aβ₄₂. This cholesterol-driven elevation of Aβ₄₂ is linked to abnormalities in neuronal processes, including endosomal enlargement, vesicular transport deficits, and gene expression changes. These disruptions can impair synaptic function by interfering with proper intracellular trafficking, signaling, and communication in neurons, contributing to the early pathology of sporadic AD (Marquer et al., 2014; Table 3). Aβ forms a complex with Cu²⁺, inducing cholesterol oxidase-like activity through proton transfer from cholesterol (Yoshimoto et al., 2005). This complex catalytically produces 4-cholesten-3-one, which has a strong potential to disturb or modulate neurotransmission at both the presynaptic and postsynaptic levels (Puglielli et al., 2005; Petrov, 2024). Furthermore, targeting β-secretase or γ-secretase has been explored as a mechanism in AD drug development, with chronic γ-secretase inhibition reducing neuronal cholesterol levels and impairing synaptic function (Fu et al., 2023).

Table 3.

Lipid alterations and impact on synaptic dysfunction in central nervous system diseases

Lipid alterations	Effects on synapses	Associated pathological factors	References
Cholesterol decreased	Lowering the presynaptic release	Chronic suppression of γ-secretase	Essayan-Perez and Südhof, 2023
Cholesterol increased	Vesicular transport deficits	Aβ42 over-production	Marquer et al., 2014
Sphingomyelin decreased	Impaired synaptic plasticity	ABCA7 deficiency	Iqbal et al., 2022
Phospholipid reduced	Neurotransmitter release and synaptic plasticity impairment	Accumulation of α-synuclein	Karaki et al., 2022; Zhao et al., 2024; Burré et al., 2018
Cholesterol decreased	Glutamate release and synaptic vesicle recycling alteration	Exogenous α-synuclein	Lazarevic et al., 2022
Cholesterol decreased	Synaptic transmission dysfunction	SOD1G93A mutants	Spalloni et al., 2013
Cholesterol increased	Increased neuronal apoptosis	Phenotype polarization in microglia	Wei et al., 2024b; Wei et al., 2024a
Cholesterol 25-hydroxylase increase	Impaired synaptic plasticity	Pro-inflammatory responses	Jang et al., 2016

This table presents the associations between lipid alterations and changes in synaptic function, highlighting their relevance to significant pathological processes. Variations in lipids, such as cholesterol, sphingomyelin, and phospholipids, are linked to synaptic dysfunction, including alterations in plasticity, neurotransmitter release, and vesicle recycling. Aβ₄₂: Amyloid-β 42; ABCA7: ATP binding cassette subfamily A member 7; SOD1G93A: superoxide dismutase 1 glycine 93 to alanine mutation.

Ceramide, the key product in sphingolipid metabolism, can affect Aβ production and tau hyperphosphorylation. When sphingomyelinase, an enzyme that hydrolyzes SM to ceramide, is inhibited, γ-secretase activity Aβ secretion is reduced (Grimm et al., 2005). This finding may be related to the role of ceramide in promoting amyloid biogenesis in lipid rafts by stabilizing β-secretase (Puglielli et al., 2003). ABCA7 deficiency reduces brain SM levels, leading to synaptic plasticity impairments and cognitive deficits, which can be rescued by SM supplementation. These findings link ABCA7 dysfunction and SM metabolism to the pathogenesis of late-onset AD (Iqbal et al., 2022; Table 3). In combination with many other clinical studies, these findings help clarify that dysregulation of lipid metabolism, which is evident in early AD stages, may serve as an initiating mechanism, emphasizing the importance of lipid interventions in AD management (Tobeh and Bruce, 2023; Cao et al., 2024).

Synucleinopathies

Synucleinopathies, including PD, are characterized by the accumulation of fibrillized α-synuclein (α-syn) in neural tissues (Praschberger et al., 2023), particularly in presynaptic terminals. α-Syn binds to membranes via interactions of the positively charged N-terminal domain and the negatively charged surface of phospholipids (Varkey et al., 2010; Westphal and Chandra, 2013; Shi et al., 2015), influencing SV transport and dopamine release (Burré et al., 2018). This interaction requires optimal cholesterol levels, which correlates with α-syn function and minimal aggregation. α-Syn also inhibits PLD, potentially affecting membrane lipid dynamics (Braun et al., 2012; Mahapatra et al., 2021). This finding has been corroborated in in vivo and in vitro studies with PLD1 and PLD2 inhibitors (Payton et al., 2004; Gorbatyuk et al., 2010), but remains a topic of debate (Rappley et al., 2009). Vesicle trafficking and lipid-related genes are recognized risk factors for PD, suggesting a two-way relationship. The question of whether abnormal α-syn accumulation leads to impaired vesicle trafficking and lipid imbalances or results from them might be answered with both. A recent study has reported that α-syn shows a preference for binding to lysophospholipids, particularly lysophosphatidylcholine (LPC), in a manner independent of electrostatic interactions (Zhao et al., 2024). LPC plays a crucial role in maintaining α-syn in a compact conformation, significantly reducing its aggregation propensity both in vitro and in cellular environments. Conversely, a reduction in cellular LPL production is associated with increased α-syn accumulation. These findings highlight the essential role of LPLs in preserving the native conformation of α-syn and preventing its misfolding, while also suggesting a potential link between lipid metabolic dysfunction and α-syn aggregation in PD (Karaki et al., 2022; Zhao et al., 2024; Table 3). In short, the interaction of α-syn with membranes suggests that inherited membrane changes could either attract or repel α-syn, thereby affecting vesicle trafficking (Fanning et al., 2021).

Extracellular α-syn has been shown to reduce membrane cholesterol levels, reorganizing cholesterol-enriched domains and affecting SV dynamics. This leads to increased tonic SV release and decreased depolarization-evoked release of neurotransmitters like glutamate. The mechanism involves α-syn-mediated cholesterol efflux through the cholesterol transporter ABCA1, as well as the phosphorylation and dephosphorylation of synaptic scaffolding proteins like synapsin. These processes mobilize distinct SV populations within presynaptic terminals, ultimately disrupting normal synaptic activity and contributing to neurodegenerative pathology (Lazarevic et al., 2022; Table 3).

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) represent the most frequent genetic risk factor for autosomal dominant PD (Monfrini and Di Fonzo, 2017). LRRK2 has been shown to be association with various membranous and vesicular structures, such as lysosomes, endosomes, SVs, and mitochondria, indicating potential interactions with lipids or lipid-binding proteins (Piccoli et al., 2011). Studies using rodent models with LRRK2 deficiency have demonstrated alterations in lipid composition, including sphingolipids, phospholipids, sterols, and glycerolipids (Ferrazza et al., 2016). Notably, Rab GTPases, which are substrates of LRRK2, play critical roles in SV trafficking. For instance, Rab3, a substrate of LRRK2, facilitates SV exocytosis, while Rab5 and Rab35 are involved in vesicle recycling (Binotti et al., 2016). Rab5-mediated phospholipid metabolism is essential for uncoating of clathrin-coated vesicles, a prerequisite for endocytosis (Semerdjieva et al., 2008). LRRK2 inhibitors and statins have been recently explored as potential therapeutic agents for PD (Galper et al., 2022). However, the lipid-modulating effects of these treatments and their precise benefits for PD patients remain under active investigation.

Amyotrophic lateral sclerosis

ALS is a neurodegenerative disease marked by progressive loss of upper motor neurons within the motor cortex and lower motor neurons located in the brainstem and spinal cord. Several studies have conducted quantitative metabolomics and lipidomics analyses of patients with ALS or ALS mouse models (Goutman et al., 2022a; Alessenko et al., 2023), consistently revealing dysregulated lipid metabolism during ALS. Dysregulated lipid metabolism can lead to the accumulation of ceramides, arachidonic acid, and LPC, among various lipid compounds that negatively affect motor neurons (van Rheenen et al., 2021). Conversely, elevations in potentially beneficial lipids like glucosylceramides, coupled with the activation of S1P-mediated signaling, may confer protection against ALS (Agrawal et al., 2022). The key findings of previous studies have highlighted alterations in multiple lipid-related pathways, including long-chain saturated FAs, PUFAs (n3 and n6), monounsaturated FAs, and FA metabolism intermediates such as acylcarnitines and SM (Goutman et al., 2022b). The genes TARDBP and C9ORF72, which are linked to ALS, have been shown to play important roles in lipid metabolism. In mouse models, TARDBP knockout has been found to reduce fat storage, enhance lipid oxidation, and alter the expression of genes associated with obesity (Chiang et al., 2010). Meanwhile, C9ORF72 influences lipid metabolism by interacting with coactivator-associated arginine methyltransferase 1, an epigenetic regulator involved in activating autophagy and FA synthesis genes (Liu et al., 2018). These findings suggest that disruptions in lipid metabolism are frequently associated with ALS pathology, affecting both genetic and tissue-specific processes. Mutations in the SPTLC1 (SPT long chain subunit 1) gene, crucial for sphingolipid biosynthesis, have been linked to ALS (Johnson et al., 2021). Additionally, the accumulation of ceramides may lead to lipid-raft disruption at neuromuscular junctions, which could be an early event in ALS. The cholesterol derivative, 25-hydroxycholesterol (25-HC), may serve as a molecule that restores the membrane and functional properties of neuromuscular junctions (Zakyrjanova et al., 2021).

Lipid metabolism is essential for maintaining energy balance in neurons and astrocytes, and its disruption is strongly implicated in the progression of ALS. Oxidative stress plays an important role in driving pathology, since lipid-derived oxidative intermediates are found to be elevated in cerebrospinal fluid (Tohgi et al., 1999; Mitsumoto et al., 2008). Under normal conditions, oxidative and metabolic stress in the CNS remain low (Almeida et al., 2004). However, ALS is characterized by high metabolism and high energy demands. Despite the increased energy requirements, patients with ALS often show reduced nutritional intake, which is associated with malnutrition, loss of appetite, and hypothalamic atrophy. These clinical manifestations also represent the progression of the disease to some extent (Ngo et al., 2019; López-Gómez et al., 2021). Research using ALS models has demonstrated a decline in glucose levels within the brain and spinal cord (Tefera et al., 2019), alongside reduced lactate transport and synthesis (Lee et al., 2012b), mitochondrial damage (Magrané et al., 2014), and impaired electron transport chain function (Smith et al., 2019). These findings suggest that the CNS in ALS has diminished ability to metabolize glucose. To address this energy-shortage issue, the body may turn to alternative energy sources, particularly FAs. The elevated levels of ketone bodies in the cerebrospinal fluid of ALS patients and the increased lipid breakdown in ALS mouse models indicate a systemic reliance on lipid metabolism (Kumar et al., 2010; Dodge et al., 2013). However, this metabolic shift comes at a cost, since the higher oxidative stress generated by β-oxidation further compromises the already vulnerable CNS. Lipid peroxidation is notably elevated in ALS, reinforcing the connection between lipid metabolism and oxidative damage, which is a key driver of disease pathology (Simpson et al., 2004; Miana-Mena et al., 2011). Chaves-Filho et al. (2019) performed lipidomics studies and highlighted substantial changes in spinal cord lipid composition in ALS models, including reduced cardiolipin levels and a sixfold increase in the levels of cholesterol esters. The decline in cardiolipins is linked to mitochondrial dysfunction and heightened production of ROS due to lipid oxidation. Conversely, the rise in cholesterol esters may reflect an adaptive response, wherein astrocytes store lipids in LDs to shield them from peroxidation. Therefore, while lipid metabolism dysregulation contributes to ALS pathology, some lipid alterations may represent protective mechanisms aimed at reducing further damage to the CNS.

Lipid changes in the lipid raft and alterations in glutamate signaling pathways contribute to ALS pathogenesis (Agrawal et al., 2022). Depletion of membrane cholesterol diminishes NMDA-induced currents, with a more pronounced reduction observed in SOD1G93A mutants. This finding underscores the involvement of the glutamate signaling pathway in ALS (Spalloni et al., 2013). Cholesterol-induced modulation of NMDA receptor function seems to occur through alterations in the probability of ion channel opening, rather than being driven by changes in the protein composition of lipid rafts (Korinek et al., 2015). However, additional studies are necessary to clarify the underlying mechanism of this cholesterol-NMDA receptor interaction and to assess how significantly this mechanism is disrupted in the context of ALS (Table 3). The role of cholesterol and its metabolites in various CNS disorders has been extensively investigated. Research directly addressing the contribution of membrane cholesterol to ALS mechanisms is limited. Nonetheless, a growing body of evidence indicates a positive association between higher plasma cholesterol levels and extended survival in ALS patients (Hop et al., 2022). A recent study demonstrated that cholesterol accumulation in skeletal muscle correlates with disease severity and motor dysfunction (Sapaly et al., 2024). Altered cholesterol metabolism is already evident in the presymptomatic stage, as indicated by the overexpression of lysosomal cholesterol transporters Niemann-Pick type C1 (NPC1) and 2 (NPC2) in patients with ALS and asymptomatic ALS-mutation carriers. Cholesterol accumulation in the lysosomal compartment indicates dysfunction in the NPC1/2 system, which disrupts cellular cholesterol transfer (Sapaly et al., 2024). Furthermore, NPC1 inhibition in myotubes leads to a shift toward FA reliance, reflecting the metabolic defects associated with ALS. Targeting NPC1/2 dysfunction could serve as a therapeutic strategy to restore energy metabolism and slow the progression of ALS.

Brain injuries, demyelinating diseases and inflammation

During brain injuries such as traumatic brain injury (TBI) or ischemia, lipid metabolism and signaling pathways are significantly disrupted, leading to various pathological outcomes. White matter demyelination is a crucial pathological process following TBI, with a strong correlation between the severity of demyelination and neurological outcomes (Spitz et al., 2013). Myelin is rich in sphingolipids and cholesterol, and studies have found that TBI induces significant alterations in lipid metabolism, including increased free FAs and decreased phospholipid and cholesterol levels (Demediuk et al., 1988; Lai et al., 2022). Additionally, TREM2 in microglia can accelerate the proliferation of oligodendrocyte precursor cells via the DHCR24/LXR pathway, promoting neurofunctional recovery after brain injury (Li et al., 2024). This injury also induces increased expression of Cyp46A1 in microglia and astrocytes, potentially participating in the clearance of damaged cell membranes and aiding in the reestablishment of brain cholesterol homeostasis. Moreover, abnormal lipid metabolism in microglia has been observed in in vitro cellular models of cerebral ischemia. In ischemic brain injury, LD accumulation and excessive cholesterol synthesis may promote neuronal death and inflammatory responses (Sapaly et al., 2024; Wei et al., 2024; Table 3).

In demyelinating diseases such as multiple sclerosis, lipids play a crucial role in regulating synaptic function and repair. After acute demyelination, oligodendrocytes import cholesterol from damaged myelin that has been recycled by phagocytic microglia. This cholesterol is used to form new myelin membranes, which indirectly supports synaptic function by restoring axonal insulation and conduction (Berghoff et al., 2021b). During chronic demyelination, oligodendrocytes rely on their own cholesterol synthesis for remyelination. Cholesterol-rich SVs released from callosal axons may act as signals to oligodendrocyte precursor cells, promoting their proliferation and differentiation, which is critical for synaptic repair and activity-dependent myelination (Pfeiffer et al., 2019; Neely et al., 2022). Neurons themselves contribute to cholesterol synthesis for remyelination, highlighting their role in maintaining synaptic integrity and function (Berghoff et al., 2021a). In peripheral axons, cholesterol trafficking is regulated by peripheral myelin protein 22. The absence of myelin protein 22 leads to reduced membrane cholesterol, which disrupts synaptic stability by increasing membrane capacitance and decreasing resistance (Zhou et al., 2019). FAs, particularly PUFAs, are key modulators of synaptic recovery. Treatment with omega-3 PUFAs improves lesion recovery and promotes remyelination. This process likely restores synaptic function by reducing inflammation and supporting lipid mediator synthesis (Penkert et al., 2021).

Cholesterol 25-hydroxylase (CH25H) expression and 25-HC production in microglia greatly increases during inflammation and ultimately affects neuronal function (Wong et al., 2020; Izumi et al., 2021). 25-HC amplifies pro-inflammatory responses, particularly IL-1β production, through mechanisms involving the NLRP3 inflammasome (Jang et al., 2016; Table 3). These effects are more pronounced in the presence of the apoE4 isoform and contribute to synaptic dysfunction and neurodegeneration. 25-HC disrupts hippocampal LTP and impairs learning and memory in mice. These disruptions are linked to NMDA receptor-dependent metaplasticity (Izumi et al., 2021). Additionally, 25-HC modulates microglial chemotaxis and phagocytosis, contributing to neurodegenerative processes (Long et al., 2021).

Cellular senescence is a kind of cellular state triggered by endogenous or exogenous stimuli. Aging impacts lipid metabolism in both neurons and glia, leading to changes in lipid composition. For example, aging alters the lipid composition of neuron membranes, affecting membrane fusion, neurotransmitter receptor dynamics, and survival signaling pathways, which contribute to cognitive decline and neuron survival (Ledesma et al., 2012). Additionally, in aging mice, hippocampal microglia are enriched with LDs and promote the secretion of pro-inflammatory factors such as CCL4, TNF, IL-1α, IL-1β, and cerebrospinal fluid 1 (Marschallinger et al., 2020b). Altered lactate metabolism in neurons and glia with age affects the tricarboxylic acid cycle and leads to increased neutral lipid accumulation, impacting memory and survival in an age-dependent manner (Frame et al., 2023).

Psychiatric disorders

PI3K, a key regulator of PI metabolism, plays a critical role in lipid signaling pathways that influence neurodevelopment and neurodegeneration. The balance between PI4,5P2 and PI3,4,5P3 is essential for normal neuronal function, and disruptions in this balance have been implicated in various neuropsychiatric disorders (Tariq and Luikart, 2021). In autism spectrum disorders, aberrant lipid signaling through the PI3K pathway contributes to pathological outcomes, including deficits in social interaction, impaired language development, restricted interests, and repetitive behaviors. Studies have shown that dysfunction in PI3K is closely linked to autism spectrum disorders, with somatic mutations in its catalytic subunit causing conditions such as megalencephaly and hemimegalencephaly (Jansen et al., 2015). These structural abnormalities are frequently associated with developmental delays and epilepsy (Lee et al., 2012a). Similarly, the dysregulation of the PI3K signaling pathway is closely associated with schizophrenia. In patients with schizophrenia, the transcription of the gene PIK3C3, which encodes the PI3K subunit, is reduced, which may lead to impaired lipid signaling (Duan et al., 2005). In addition, two major susceptibility factors for schizophrenia, neuromodulin-1 and schizophrenia-interfering protein-1, converge on the PI3K/Akt pathway, linking PI3K dysfunction to abnormal neuronal development and plasticity in this disease (Seshadri et al., 2010). Lysophosphatidic acid (LPA) is a bioactive lipid signaling molecule involved in the regulation of synaptic activity and the pathophysiology of mental disorders. The autotaxin enzyme that synthesizes LPA is selectively localized to excitatory synapses and is absent in inhibitory synapses (Thalman et al., 2020). This selective localization suggests that LPA signaling plays a specific role in modulating excitatory synaptic activity. Dysregulation of LPA signaling has been associated with altered neuronal communication and plasticity, which are hallmarks of several neuropsychiatric disorders (Mirendil et al., 2015). These findings underscore the importance of phospholipid metabolism in maintaining synaptic function and its potential contribution to the development of psychiatric conditions.

Cholesterol, a critical component of neuronal membranes, plays a significant role in modulating synaptic signaling and plasticity (Ling et al., 2024). A recent study has shown that cholesterol levels influence the activity of BDNF and its receptor, tyrosine kinase receptor B. Elevated membrane cholesterol can impair tyrosine kinase receptor B signaling, which is essential for neuronal plasticity and antidepressant responses. However, this impairment can be reversed in the presence of antidepressants, indicating a complex interaction between cholesterol and synaptic signaling pathways (Casarotto et al., 2021). These findings highlight the importance of lipid composition, particularly cholesterol, in regulating neuronal function and plasticity. Dysregulation of cholesterol metabolism may contribute to the pathogenesis of neuropsychiatric disorders by impairing critical signaling pathways involved in synaptic communication and neuronal health (Fisher et al., 2024). In conclusion, alterations in lipid species and lipid metabolism are present in the pathogenesis and progression of many neurological diseases. Notably, lipid molecules may act by interfering with abnormal protein production, binding to synaptic receptors, and disrupting metabolic pathways. These findings highlight the importance of early intervention with lipid-centered strategies to improve efficacy.

Lipid-Targeted Treatment Strategies for Neurological Disorders

LXR functions as an intracellular cholesterol level sensor, promoting the transcription of ABCA1 and ApoE, pivotal in lipid transport and metabolism (Tavazoie et al., 2018). Previous studies have highlighted the therapeutic potential of LXR intervention in AD (Chiang et al., 2022; Zhang et al., 2024a). Agonists such as GW3965 and T0901317 enhance Aβ elimination, mitigate neuroinflammation, and alleviate cognitive deficits in AD mice, primarily through ABCA1 and ApoE pathways (Zelcer et al., 2007; Litvinchuk et al., 2024; Figure 4). Bexarotene, a retinoid X receptor agonist, enhances Aβ clearance and cognitive function in AD mouse models by upregulating ABCA1 activity and reversing ApoE4 hypolipidation (Boehm-Cagan and Michaelson, 2014). However, a clinical study on Bexarotene has shown variable efficacy (Cummings et al., 2016).

Additionally, statins, commonly prescribed for cholesterol management through inhibition of the enzyme HMG CoA reductase, have shown potential in reducing AD risk, although clinical trial results remain inconclusive (Arvanitakis et al., 2008; Feldman et al., 2010; Figure 4). Schultz et al. (2018) attributed this difference to the independent effects of cholesterol in the central and peripheral systems. Recent analyses of the UK Biobank database suggest that being an ApoE4 carrier, age, and sex are also factors influencing the AD risk profile of statin users (Li et al., 2010; Geifman et al., 2017; Dagliati et al., 2021). These findings support the need for a precise and personalized approach when assessing the efficacy of cholesterol-lowering drugs in AD.

The brain-specific enzyme CYP46A1 facilitates cholesterol clearance (Brown et al., 2004), with its activator, Efavirenz, showing promise in enhancing cholesterol metabolism and ameliorating behavioral deficits in early-stage AD patients (Lerner et al., 2022; Figure 5). Recent studies indicated that reducing cholesterol esters through CYP46A1 activity effectively mitigates Aβ and tau pathology in neurons, with better tolerance observed compared to statins (van der Kant et al., 2019). Moreover, CYP46A1 activators demonstrate potential in ameliorating behavioral deficits in mouse models of AD, enhancing neuron cholesterol metabolism, and augmenting specific presynaptic and postsynaptic proteins (Petrov et al., 2019).

Lipid peroxidation can occur enzymatically, through enzymes such as LOX and cytochrome P450s, or non-enzymatically, via free radical-induced peroxidation, autoxidation, and photodegradation. Lipid peroxides are highly damaging to cells as they disrupt the thickness, permeability, and structure of membrane bilayers. PUFAs are common components of phospholipids and frequent targets of lipid peroxidation. The bis-allylic sites of PUFAs are particularly susceptible to damage induced by free radicals or non-radical species, triggering the non-enzymatic oxidation of lipids (Mortensen et al., 2023). Lipid peroxidation occurs when ROS interact with PUFAs, producing excessive lipid peroxides that are toxic to cells by disrupting membrane structure, bioenergetic processes, signaling, and membrane integrity. The brain is particularly susceptible due to its high PUFA content and oxygen consumption (Conrad et al., 2018). Targeting fatty acid synthase (FASN) inhibition emerges as a promising avenue for mitigating lipid peroxidation in AD patients (Khan et al., 2013). An in vitro study demonstrated that the FASN inhibitor CMS121 effectively counteracts lipid peroxidation in neuronal cells mediated by RAS-selective lethal 3 (Ates et al., 2020). Furthermore, CMS121 exhibits efficacy in inhibiting LPS-induced lipid peroxidation in microglial-like cells (Ayala et al., 2014). Consistent with its mechanistic action, CMS121 modulates lipid profiles in AD mouse models, notably reducing endocannabinoid, FA, and PUFA levels, while significantly elevating neuroapoptotic-related ceramide levels (Ates et al., 2020). The most important group of enzymes catalyzing the dioxygenation of PUFAs to form lipid hydroperoxides are LOXs (Wang et al., 2015). In AD patients, LOXs have been implicated in inflammation, and their levels are elevated. Meanwhile, CMS121 has been found to inhibit the activity of multiple LOXs (Currais et al., 2024). Therefore, the changes in FA and PUFA levels observed with CMS121 treatment in AD may result from a combination of multiple factors. These findings underscore the promising efficacy of CMS121 both in vitro and in vivo, paving the way for Phase I clinical trials in AD therapy (ClinicalTrials.gov, 2022d).

Fingolimod, a sphingolipid drug in clinical trials for ALS (Berry et al., 2017), shows promise in enhancing synaptic protein abundance and improving cognitive function in AD models. In detail, upon binding to S1PR receptors, fingolimod induces the formation of fingolimod-phosphate, an analog of S1P with anti-apoptotic properties. This mechanism effectively regulates the abundance of S1PR receptors on the cell surface, offering promising therapeutic potential (O’Sullivan and Dev, 2017). Others have also shown that fingolimod enhances the abundance of synaptic proteins in the cortex of APP/PS1 mice, leading to improved cognitive function (Kartalou et al., 2020; Fagan et al., 2022).

Lipid metabolism plays a significant role in the pathogenesis and progression of ALS. Dyslipidemia, particularly elevated levels of LDL cholesterol, may have a protective effect on ALS patients (Goldstein et al., 2008). HFDs and specific lipid metabolic interventions, such as targeting glucosylceramide synthase, show potential as therapeutic strategies (Fergani et al., 2007; Henriques et al., 2015). Various lipid species, including cholesterol, triglycerides, and FAs, have been proposed as potential biomarkers for ALS, aiding in the assessment of disease onset, progression, and prognosis. Despite some inconsistencies, there is growing acceptance that lipid dysregulation is a crucial component of ALS pathology. Further research into lipid biomarkers could enhance patient monitoring and treatment strategies.

Under pathological conditions, lipids can exert harmful effects on synapses through the involvement of various pathological factors, such as Aβ accumulation, α-syn aggregation, and pro-inflammatory responses (Cerasuolo et al., 2024; Xia et al., 2024). These factors disrupt the delicate balance between the beneficial and harmful roles of lipids, leading to synaptic damage by impairing neurotransmitter release, synaptic plasticity, and membrane stability (Table 3). This interplay between the beneficial and harmful roles of lipids is highly context-dependent, as lipids are essential for regeneration, serving as energy sources, structural components, and signaling molecules that stimulate synaptic growth (Incontro et al., 2025). Yet, when dysregulated, they contribute to synaptic dysfunction and neurodegeneration. Therapeutic strategies targeting lipids must therefore carefully navigate this balance, aiming to reduce lipid toxicity while preserving their critical physiological functions.

In summary, lipid-targeted treatment strategies for neurological disorders primarily focus on two aspects: intervening in lipid metabolism to promote lipid excretion and reduce lipid accumulation, and externally supplementing lipids. It is worth noting that when using these methods to intervene in lipid metabolism to fight against diseases, we should consider the characteristics of the patient and the risk factors of the disease.

Limitations

This review has certain limitations. We have only focused on a few key lipids, including sterols, glycerophospholipids, sphingolipids, and FAs, and their roles in synaptic function and neurological diseases. Due to the vast diversity of lipid classes, we did not cover all types of lipids. Lipids cannot be directly and specifically regulated in their expression or studied using classical protein research tools. The challenges of conducting in vivo studies are even greater. Therefore, the detailed molecular mechanisms by which lipids regulate diseases have not been fully elucidated.

Conclusions

In recent years, the complex relationship between lipids and synaptic function has attracted widespread attention, particularly regarding their roles in neural regeneration and neurological diseases (Incontro et al., 2025). This review highlights the multifaceted roles of various lipid classes, including sterols, glycerophospholipids, sphingolipids, and FAs, in modulating synaptic function and their implications for neurodegenerative diseases.

The vast structural diversity of lipids underscores their multifaceted roles in neuronal function. Lipids play dual roles in neurons: they act as essential building blocks of neuronal membranes and function as bioactive signaling molecules. This duality is particularly evident in the intricate process of synaptic transmission (Gopalakrishnan et al., 2010). The structural integrity of synapses depends on the proper composition of lipids, particularly during synaptic development and regeneration. In glial cells, lipids are pivotal for energy metabolism and regulate glial responses to synaptic activity, thereby maintaining neural homeostasis. For example, astrocytes orchestrate complex lipid-centered metabolic processes to support neighboring neurons, safeguarding them during periods of cellular stress (Tracey et al., 2018). However, disruptions in lipid metabolism within microglial cells can compromise their chemotaxis and phagocytic functions, impairing their ability to clear damaged synapses and debris effectively (Keren-Shaul et al., 2017; Flury et al., 2024). Oligodendrocytes, furthermore, are primarily responsible for synthesizing lipid-rich myelin sheaths and responding to neuronal activity (Cawley et al., 2021). In summary, lipids directly influence the regeneration process of the CNS by supporting axonal growth, promoting myelin sheath regeneration through myelin synthesis, and facilitating synaptic repair via lipid-mediated signaling and metabolic support from glial cells. Several future research avenues can enhance our understanding of the role of lipids in synapses. First, there is an urgent need to develop advanced imaging techniques to monitor lipid dynamics in real time within living organisms (Park et al., 2023). The application of super-resolution microscopy, combined with single-particle tracking, enables researchers to visualize lipid heterogeneity and dynamics within the plasma membrane and subcellular membranes (Zhanghao et al., 2020; Lorizate et al., 2021). This approach will enable researchers to observe lipid interactions within the CNS under physiological and pathological conditions, thereby gaining deeper insights into their roles in synaptic function and regeneration. Furthermore, an interdisciplinary approach that combines lipidomics, genomics, and proteomics can provide valuable insights into the complex regulatory networks of lipid metabolism in the CNS. By integrating data from multiple omics layers, we can identify new lipid-related biomarkers and therapeutic targets for neurodegenerative diseases. Additionally, developing more sensitive lipid analysis methods, particularly mass spectrometry, is crucial (Merrill et al., 2017; Chorev and Robinson, 2020). These techniques can help uncover the structural details of synaptic lipid composition.

This review highlights the role of lipids in synaptic function and their impact on neurological disorders. The novelty of this review lies in its emphasis on the interactions between different lipid classes and their collective influence on synaptic health, rather than focusing solely on individual lipids. Additionally, the review highlights the relationship between astrocytes, microglia, and oligodendrocytes with lipids and synapses under both physiological and pathological conditions (Victor et al., 2022). The role of astrocytes in lipid metabolism and their ability to support neuronal function during stress is particularly noteworthy (Ioannou et al., 2019). Future research should focus on elucidating the mechanisms by which astrocytes and microglia regulate lipid homeostasis and their implications for synaptic plasticity and regeneration.

Given the pivotal role of lipids, a plethora of drugs targeting lipid pathways have been developed, with a predominant focus on cholesterol metabolism in astrocytes and the supplementation of FAs. Furthermore, sphingolipid metabolism presents promising therapeutic targets, including the depletion of GSLs and modulation of S1P-metabolizing enzymes (Dodge et al., 2015; Di Pardo et al., 2017; Tringali and Giussani, 2022). In addition, many of the neuroprotective effects of lipid modulation methods are related to their indirect effects on peripheral metabolism. This suggests that the potential neurological and peripheral side effects need to be evaluated in detail when used in the nervous system.

Funding Statement

Funding: This work was supported by the National Natural Science Foundation of China, No. 82201568 (to QQ); Capital’s Funds for Health Improvement and Research, No. 2024-2-1031 (to QQ); Beijing Nova Program, No. 20240484566 (to QQ).

Data availability statement:

Not applicable.