AD serves as the primary cause of dementia, accounting for 60–70% of all instances. Furthermore, the prevalence of this ailment increases as individuals age [3]. The estimated number of people living with dementia globally was reported to be 57.4 million in 2019 and is expected to reach 153 million by 2050 [7].

In individuals afflicted with AD, there are discernible pathological modifications that transpire within cells as well as outside of cells. The intracellular build-up of hyperphosphorylated tau protein gives rise to the development of neurofibrillary tangles, whereas the extracellular build-up of Aβ protein gives rise to the appearance of Aβ plaques. The prevailing viewpoint in the realm of pathophysiology posits that the etiology of AD is intricately interconnected with Aβ and tau.The presence of Aβ and tau proteins, which deviate from the norm, initiates a series of subsequent occurrences, including inflammation and disturbances in cellular pathways such as lipid and glucose metabolism. The excessive production of Aβ or the hindrance of its removal has been associated with a heightened susceptibility to AD.

In the early stages of AD, prospective individuals manifest elevated levels of hyperphosphorylated tau in their cerebrospinal fluid, a phenomenon that disrupts microtubules and subsequently affects axonal transport and neural transmission [8], thereby contributing to cognitive decline. Synapses also play a significant role in the pathology of AD. Increasing evidence suggests that synaptic loss is an early disease process caused by the accumulation of soluble Aβ and phosphorylated tau protein, as well as increased production of free radicals by synaptic mitochondria. Moreover, extracellular Aβ aggregates at both postsynaptic spines and presynaptic spines, with a higher abundance observed at postsynaptic terminals. Further damage to glutamate transport can lead to dendritic spine loss [9]. Additionally, extracellular tau is involved in long-term plasticity by serving as a substrate for Glycogen Synthase Kinase 3β and p38 Mitogen-Activated Protein Kinase, further regulating synaptic function [10].

It is crucial to acknowledge that these two factors are not independent, as there exists evidence indicating that Aβ-induced neurotoxicity relies on the presence of tau [11]. Tau may contribute to Aβ-induced harm via two mechanisms. First, tau plays a physiological role in the disruption of neural network activity caused by diverse pathogenic triggers [12, 13]. Second, Aβ modifies the post-translational modifications (PTMs) or distribution of tau, thereby converting tau into an active agent in the development of Aβ-induced neuronal dysfunction [14] (Fig. 1).

The transcription of the amyloid precursor protein (APP) gene leads to the cleavage of APP by α- and γ-secretases in the non-amyloidogenic pathway (plasma membrane) or by β- and γ-secretases in the amyloidogenic pathway (endosomal/lysosomal system), resulting in the extracellular release of amyloid beta (Aβ) peptide. Aβ monomers have the potential to form Aβ oligomers, which can fibrillize into Aβ fibrils under normal physiological conditions. However, under pathological conditions associated with Alzheimer’s disease (AD), Aβ aggregates can induce Tau-dependent neurotoxicity. The transcription and translation of the MAPT gene results in the production of Tau protein, which undergoes diverse post-translational modifications (PTMs) in various forms within the cell. In normal physiological conditions, the microtubule-binding domain (MTBD) of Tau binds to microtubules, thereby stabilizing them. However, in the presence of AD pathology, Tau is hyperphosphorylated, a process that can be influenced by Aβ aggregates, resulting in a reduction in the affinity of Tau for microtubules and rendering them unstable. Furthermore, hyperphosphorylated Tau can form neurofibrillary tangles in the cytoplasm, leading to cellular toxicity

Moreover, recent research indicates that disturbances in lipid metabolism may interact with tau and Aβ pathology, intensifying neuronal injury and cognitive deterioration in AD. Lipid metabolism is intricately connected to AD through various mechanisms such as neuroinflammation, oxidative stress, mitochondrial dysfunction, and impaired synaptic transmission [15, 16]. Additionally, lipid metabolism plays a role in the exacerbation of neuronal damage and cognitive decline in AD by influencing Aβ and Tau pathology [17]. Products of lipid peroxidation and inflammatory mediators resulting from impaired lipid metabolism have the potential to exacerbate tau hyperphosphorylation and amyloid beta aggregation, thereby perpetuating a detrimental cycle of neurodegeneration.

Astrocytes, derived from radial glial cells situated in the subventricular zone of the brain, constitute the predominant, intricate, and extensively interconnected non-neuronal cell population within the CNS. By means of neurotransmitter-mediated communication, astrocytes can directly modulate the stability, functionality, and adaptability of neurons [18]. Astrocytes possess the ability to indirectly modulate synaptic function by facilitating the phagocytosis of synaptic proteins by microglia via the secretion of IL-33 [19]. Additionally, they contribute to the maintenance of cellular ion homeostasis by engaging in the elimination of synapses and extracellular K + from axons through the involvement of membrane Na + /K + -ATPase. The Na + /K + -ATPase α2 and β2 isoforms are among the highest expressed proteins in hippocampal astrocytes, and its ability to respond directly to elevated the K + concentration in the extracellular space and the associated membrane depolarization makes it uniquely poised toward facilitating K + clearance during activity-evoked K + transients in the extracellular space [20].

Blood–brain barrier (BBB) is centrally positioned within the neurovascular unit (NVU). Different cell types of NVU, including astrocytes and microglia, regulate BBB integrity, cerebral blood flow, and participate in angiogenesis and neurogenesis. Astrocytes secrete apolipoprotein E (ApoE) to signal pericytes via low-density lipoprotein receptor-related protein-1 (LRP1), which suppress the activation of cyclophilin A-matrix metalloproteinase 9 BBB-degrading pathway. LRP1 binds AD’s Aβ toxin and mediates its brain-to-blood clearance. LRP1 levels at the BBB are diminished in AD mouse models and AD patients’ brains contributing to Aβ accumulation in the brain and activation of BBB-degrading pathway [21]. The events within microglia–astrocyte interaction include direct contact, cytokine secretion, complement-mediated interaction, receptor regulation, and exocytosis. The ion channels and ATP-mediated Ca2 + conduction may be also involved [22].

In contemporary times, scholarly inquiries pertaining to astrocytes have shifted from examining epigenetic variability to performing physiological examinations, encompassing the assessment of Ca2 + activity, ion buffering, gap junction coupling, and the expression of glutamate receptors [23]. A notable aspect of interest in astrocyte research has been their metabolic processes, as astrocytes play a pivotal role in the production of neuronal glycogen, which serves as the primary energy reserve in the brain [24]. Additionally, the lactate generated by astrocytes can function as a substrate for oxidation and as a signaling molecule for neurons [25].

Changes in astrocyte function can potentially contribute to the progression of various pathologies in the cerebral region. Among these, multiple sclerosis (MS) is characterized by the presence of persistent demyelinating lesions, axonal atrophy, widespread and localized demyelination of gray matter, and neurodegeneration caused by the depletion of oligodendrocytes and myelin. The acceleration of MS development has been observed through the activation of astrocytes by Th1, Th17, and Th1-like Th17 inflammatory cytokines, resulting in the disruption of the BBB, recruitment of leukocytes, and impairment of communication between neurons and oligodendrocytes [26]. Epilepsy is distinguished by the occurrence of unpredictable recurrent seizures, which are attributed to hypersynchronized excitatory neuronal discharges. The dysregulation of astrocytic potassium channels, resulting in an imbalance of potassium levels and impaired glutamate uptake, plays a significant role in the pathogenesis of epilepsy [27]. Additionally, the overexpression of adenosine kinase in astrocytes, leading to enhanced adenosine clearance, is a pathological hallmark of temporal lobe epilepsy.

Astrocytes have been implicated in a range of neurodegenerative disorders, such as AD, Huntington’s disease (HD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS). The potential association between astrocytes and these diseases can be attributed to their involvement in protein aggregation, dysregulation of calcium and ion homeostasis, synaptic transmission, and impairment of energy metabolism [28].

HD is distinguished by the presence of chorea, emotional disturbances, and a gradual decline in cognitive function. This neurodegenerative disorder is caused by the expansion of CAG repeat sequences in the huntingtin gene. HD astrocytes exhibit a lower expression of excitatory amino acid transporter 2 (EAAT2) mRNA and protein compared to normal controls [29, 30]. This reduction in EAAT2 levels leads to a decrease in glutamate uptake, resulting in chronic glutamate stimulation within the brain and subsequent neuronal degeneration [31]. Moreover, the presence of mitochondrial damage in astrocytes located in the striatum, along with the compromised mitochondrial bioenergetics and dynamics caused by the mutated huntingtin protein, can potentially worsen the process of neurodegeneration in HD patients [32]. This ultimately leads to disturbances in lipid metabolism within the brains of individuals affected by HD.

PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by the abnormal accumulation of misfolded α-synuclein in structures known as Lewy bodies.

The transfer of fibrillar α-synuclein from neurons to astrocytes demonstrates a higher level of efficiency, whereas the efficacy of transfer from astrocytes to neurons is comparatively lower. Moreover, astrocytes exhibit a greater proficiency in the degradation of fibrillar α-synuclein than neurons, suggesting that astrocytes may exert neuroprotective effects by capturing and breaking down pathological α-synuclein [33].

ALS, a prevalent paralytic disorder, typically presents in adulthood and is characterized by the degeneration of motor neurons within the CNS. Previous studies have demonstrated a reduction in the expression of glutamate transporter GLT1 and lactate transporter monocarboxylate transporter 1 (MCT1) in astrocytes containing the ALS-associated mutant superoxide dismutase-1 (SOD1) [34].

The association between astrocytes and AD has been extensively examined, revealing the aggregation of astrocytes around and within Aβ plaques in the CNS of AD patients. This occurrence has the potential to initiate neuroinflammation through various signaling pathways [35].

The human brain, being the second-largest organ rich in lipids, exhibits a noteworthy association between lipid metabolism encompassing FAs and cholesterol metabolism, and the maintenance of brain energy equilibrium, oxidative stress, and neuroinflammation.

FAs enter astrocytes through specific transport proteins, becoming lipid droplets (LDs) stored in the endoplasmic reticulum. They are then converted into fatty acyl-CoAs, which are transported into the mitochondria to participate in energy-producing pathways like β-oxidation and the tricarboxylic acid (TCA) cycle. The synthesis of FAs involves converting acetyl coenzyme A into various FAs through a series of enzymatic reactions, leading to the production of molecules of different lengths and saturation. Astrocytes also produce ketone bodies for neuronal energy and may transport FAs to support myelin formation or regeneration, with microglia also aiding in managing excess FAs. Notably, LDs play a pivotal role in governing neurogenesis, synaptic function, and brain inflammation [36] (Fig. 2).

The brain’s fatty acid homeostasis is centred on astrocytes. The source of astrocyte fatty acids is the blood–brain barrier and neurons overproducing fatty acids in response to neural stimulation, which enter the cell via fatty acid transport protein (FATP), fatty acid binding protein (FABP) and apolipoprotein E, and form lipid droplets (LDs) for storage in the endoplasmic reticulum. Fatty acids are converted to fatty acyl-CoAs (FA-CoAs) by a family of acyl-CoA synthetases (ACS). Carnitine palmitoyl transferases (CPT) and carnitine-acylcarnitine translocases (CAT) translocate FA-CoAs into the mitochondrial matrix, where they participate in β-oxidation and the tricarboxylic acid (TCA) cycle. Fatty acid synthesis begins with the conversion of acetyl coenzyme A to malonyl coenzyme A, which is then extended to form C16:0-CoA, a reaction that requires the participation of acetyl coenzyme A carboxylases (ACCs), ATP citrate lyase (ACLY), and fatty acid synthase (FASN).Subsequent elongation and desaturation steps, catalysed by elongases (ELOVL1-7) and desaturases (Δ4,5,6,9D), form fatty acids of different carbon lengths and degrees of saturation. Ketone bodies, an intermediate product of fatty acid metabolism in astrocytes, can be transported via monocarboxylate transporter proteins (MCT) to supply energy to neurons. Microglia also perform part of the function of consuming excess fatty acids in the brain. Fatty acids produced by astrocytes may be transported to at least synaptic glial cells to participate in myelin formation or myelin regeneration

Cholesterol is prominently concentrated within the brain, where it establishes lipid raft domains and facilitates the production of steroids, vitamin D and oxysterols [37]. Cholesterol synthesis in the brain primarily occurs through the Bloch pathway in astrocytes and the Kandutsch-Russell pathway in neurons. Astrocytes produce cholesterol that binds to ApoE and is secreted into the extracellular fluid, where it is taken up by neurons, microglia, and oligodendrocytes via LDL receptors. Cholesterol is essential for energy supply, inflammation signaling, and myelin formation. Excess cholesterol is stored as cholesteryl ester in LDs after esterification. The brain interacts with peripheral tissues through the conversion of cholesterol to more hydrophilic metabolites like 24-hydroxycholesterol (24S-OH) and 27-hydroxycholesterol (27-OH), which regulate cholesterol homeostasis within the brain and also contribute to peripheral cholesterol management. These metabolites can cross the BBB and are involved in various homeostatic processes, including microglial function and liver clearance (Fig. 3).

Brain cholesterol homeostasis is to a lesser extent related to peripheral tissues, as separated by the BBB barrier. The main pathways for cholesterol synthesis in the brain are the Bloch pathway in astrocytes, where cholesterol is derived from desmosterol, and to a lesser extent the Kandutsch-Russell pathway in neurons, where cholesterol is derived from 7-dehydrocholesterol. The synthesis process that is regulated by the sterol regulatory element-binding protein 2 (SREBP-2). In astrocytes, cholesterol binds to ApoE to form lipoproteins that are secreted into the extracellular fluid via ABC transporter proteins (especially ABCA1) and finally taken up and transported to neurons, microglia, and oligodendrocytes by the two types of LDL receptors, low density lipoprotein receptor (LDLR) and low-density lipoprotein receptor-related protein (LRP). ApoE is recycled after receptor-mediated endocytosis. Cholesterol is used for energy supply, normal production of inflammation-related signals and myelin formation. To maintain cholesterol homeostasis, excess cholesterol is esterified by enzyme acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1/SOAT1) in the andoplasmic reticulum and stored as cholesterol ester (CE) in LDs. The cholesterol associated with peripheral tissues by the brain is 24-hydroxycholesterol (24S-OH) and 27-hydroxycholesterol (27-OH). The neuron-specific enzyme 24-hydroxylase (CYP46A1) converts excess cholesterol to the more hydrophilic metabolite 24S-OH, which either diffuses into the somatic circulation via the BBB or acts as a A natural endogenous agonist of liver X receptor (LXR) controls cholesterol homeostasis. 27-OH is produced mainly in peripheral tissues by the catalytic activity of CYP 27 A1, which diffuses from the circulation to the brain via the BBB and is involved in microglia homeostasis. To a lesser extent, brain cholesterol is also oxidised to 27-OH by sterol 27-hydroxylase (CYP27A1), which is then oxidised by enzyme oxysterol 7-alpha-hydroxylase (CYP7B1) to 7α-hydroxy-3-oxo-4-cholestenoic acid (7-OH-4-C), which is cleared in the liver after passing through the BBB

Notably, there is virtually no exchange of cholesterol with the peripheral circulation, due to the impermeable nature of the BBB, and thus cerebral cholesterol level is dependent on de novo synthesis by glial cells. On the contrary, certain cholesterol products with lipophilic properties, including 27-OH, can pass the BBB. Lipoproteins, including ApoE and lipoprotein lipase (LPL), have been found to have significant effects on intercellular communication, energy homeostasis, formation of the BBB, and regulation of pro- and anti-inflammatory responses. ApoE has received much attention due to the relationship of particular alleles of its gene with the risk and progression of AD. However, other lipid-binding proteins whose role in lipid homeostasis and control are less known need to be brought to the attention. ApoJ/Clusterin and ApoE are involved in the biological processes of BBB function, oxidative stress/inflammation and amyloidogenesis whereas ApoD is involved in the biological processes of oxidative stress/inflammation, lysosome, and myelin. ApoJ and ApoE transport cholesterol by linking directly to cholesterol, whereas ApoD is transported indirectly by linking to membranes [38].

Recent advancements in genome-wide association studies and transcriptomics research in the brain have revealed numerous abnormalities in lipid metabolism in neurological disorders. Notably, lipid metabolism disorders, particularly lipid peroxidation, have been linked to various neurodegenerative diseases. Significantly, mutations in the glucocerebrosidase gene increase the likelihood of inheriting PD, as glucocerebrosidase plays a crucial role in the metabolism of neuronal ceramides. Additionally, the APOE4 gene variant, a prominent genetic predisposition for AD, has been associated with cholesterol and sphingolipids [39].

The pathogenesis of several neurodegenerative disorders has been found to be closely linked to sphingolipids, which exhibit pro-apoptotic, autophagic, and inflammatory properties.

In the context of AD, it has been observed that extracellular vesicles containing sphingolipids stimulate the production of Aβ through interaction with lipid rafts. Lipid rafts are important platforms for various signaling molecules, including receptors, kinases, and adaptor proteins. Disruption of lipid rafts can lead to changes in signal cascades, affecting processes such as synaptic plasticity, neuronal survival, and inflammation. Stimulation of astrocytes with TNF-α results in the overexpression of MIP-2γ and downregulation of GLT-1 expression, leading to a redistribution of GLT-1-mediated glutamate uptake within lipid rafts [40]. These damaged signaling pathways may contribute to the development and progression of AD. APP is a transmembrane protein located on the cell membrane. Under normal conditions, it is involved in the growth, differentiation, and repair of neurons. However, in AD, APP protein undergoes abnormal metabolism and processing, resulting in the production of Aβ. Studies have shown that astrocytes carrying APOE4 can provide excessive cholesterol to neurons, promoting the expansion of lipid rafts, accumulation of APP, and the formation of Aβ [41]. γ-secretase, located on lipid rafts, can cleave APP into Aβ. When corticotropin-releasing factor, a stress response mediator, is elevated, γ-secretase is upregulated, which further increases Aβ secretion [42]. Drugs targeting lipid raft formation, such as platelet-activating factor antagonists, can enhance the intracellular degradation of Aβ [43]. Individuals with AD display higher levels of acid sphingomyelinase and acid ceramidase, resulting in increased concentrations of sphingolipids [44]. A study comparing sphingolipid concentrations in the cerebral cortex of AD patients and individuals without the disease revealed that AD patients have elevated basal levels of long-chain sphingolipids C22:0 and C24:0 [45]. Moreover, alterations in the levels of sphingolipids have been observed in individuals diagnosed with idiopathic PD, indicating a potential association between sphingolipids and the development of PD [46]. In a mouse model of PD with glucocerebrosidase mutation, the inhibition of sphingolipid synthase activity led to a reduction in the buildup of insoluble α-synuclein oligomers and ubiquitinated proteins, providing additional evidence for the connection between PD and sphingolipids [47].

The correlation between the accumulation of Bis(monoacylglycero)phosphate (BMP) in late endosome-lysosome compartments and neurodegenerative diseases has been established through research. BMPs are localized within the inner membranes of late endosomes (multivesicular bodies) and lysosomes, where they contribute to the multivesicular/lamellar morphology of the endolysosomal network. BMPs are elevated in cell types such as macrophages that rely heavily on lysosomal function [48]. In the case of AD, the upregulation of the lipid kinase Vps34, which is responsible for phosphatidylinositol 3-phosphate synthesis, leads to BMP accumulation. Similarly, in individuals carrying the LRRK2 G2019S mutation (the most common genetic determinant of PD identified to date) and experiencing cognitive decline, BMP accumulation is associated with the onset of PD [49].

Individuals diagnosed with HD and ALS display disruptions in the metabolic pathways of sphingolipids and cholesterol within the brain. Specifically, the HD group exhibited elevated levels of sphingosine-1-phosphate lyase 1 and reduced levels of sphingosine kinase 1 in the striatum and cortex compared to the normal group. Individuals with HD display heightened levels of cholesterol ester (CE) in both their tail and shell nuclei. This finding suggests that the impaired synthesis of cholesterol during the development and repair of the myelin sheath in the CNS could contribute to the pathogenesis of ALS. It is noteworthy that the composition of myelin phospholipids in SOD1 G93A rats is altered, indicating a potential compromise in lipid production by oligodendrocytes in ALS patients [50].

The protein ApoE plays a crucial role in facilitating the transportation of lipids in both the brain and periphery. Polymorphism in the APOE gene has been identified as potential risk factors for cellular dysfunction, which can result in abnormalities in calcium signaling, energy metabolism, and lipid metabolism. The relationship between APOE variants and the manifestation of AD and other proteinopathies has garnered significant scholarly attention in recent times. APOE ε2 is considered neuroprotective, whereas APOE ε4 is considered a risk factor for AD, relative to the common ApoE ε3 allele. However, these variants show different behavior, such as their main interactors (LRP1 for ApoE2 and VLDLR for ApoE4), efficiency of intracellular lipid transport (higher for ApoE2, because of the weaker bind low density lipoprotein receptor (LDLR)) or affinity for Aß (reduced for ApoE4, because of VLDLR’s lower rate in internalization of APOE–Aβ complex) [51]. Furthermore, there has been a growing scholarly interest in investigating the impact of aberrant lipid metabolism in astrocytes on the progression of neurological disorders, such as AD [52, 53].

The significance of FAs and cholesterol in astrocytes in the context of AD is noteworthy. Neurons prevent lipotoxicity by transferring their excess intracellular FAs to astrocytes via ApoE, which is transported intracellularly by binding to fatty acid-binding proteins (FABPs) and primarily stored in LDs. Subsequently, FA can be transported to mitochondria for β-oxidation. However, the accumulation of LDs caused by dysfunctional mitochondria in astrocytes and excessive FA uptake can lead to lipid metabolism disorders.

Elevated concentrations of free FAs have been recognized as a potential factor in the development of neuroinflammation, consequently heightening susceptibility to AD. Conversely, cholesterol assumes a pivotal function in synaptic physiology, as it is either synthesized by neurons or conveyed from astrocytes to neurons. Specific cholesterol metabolites, including 24-hydroxycholesterol, have demonstrated anti-inflammatory characteristics.

In AD, the presence of intracellular cholesterol buildup in astrocytes has the potential to induce lipotoxicity. Additionally, ApoE plays a crucial role as the principal carrier for lipids, encompassing FAs and cholesterol, and its ApoE4 subtype can contribute to the progression of AD through various lipid metabolic pathways.

Astrocytes obtain FAs from both exogenous and endogenous origins. Astrocytes depend on the BBB for the delivery of FAs originating from extracerebral sources. Certain FAs have the ability to permeate the BBB and be absorbed by astrocytes within the brain. Foreign substances have the ability to penetrate the brain and be absorbed by astrocytes in the form of complexes with transport proteins, like FABP, which can traverse the BBB.

Glucose and free FAs have a direct effect on neurons in the hypothalamic periventricular nucleus, which can be modulated by ketones released by astrocytes. This suggests that brain ketone levels play an important role in the uptake of exogenous FAs by astrocytes [54]. Astrocytes also have the ability to detect peripheral FAs. A decrease in the leptin pathway caused by a high-fat diet reduces the coverage of astrocytes on Pro-opiomelanocortin (POMC) neurons and increases the synaptic connections between POMC and Agouti-related peptide (AgRP) neurons, but does not affect the number of astrocytes [55]. In vitro experiments have shown that polyunsaturated fatty acids from outside the brain enter astrocytes after passing through the endothelial cell monolayer and lower layer [54]. Additionally, LDL can be engulfed by endothelial cells and regulated by astrocytes [56]. The engulfed FAs can be released by astrocytes in an HDL-like manner and transported to neurons and other glial cells. LPL, expressed in hypothalamic astrocytes, promotes the uptake of cellular lipids and lipoproteins through hydrolysis and non-hydrolysis pathways. The expression of LPL is reduced after exposure to triglycerides, resulting in a decrease in LD, which may indicate impaired uptake of lipids from peripheral, glial, and neuronal sources, potentially affecting neuronal toxicity [57]. Conversely, the specific knockout of the LPL inhibitor ANGPTL4 inhibits mitochondrial degeneration in astrocytes caused by a high-fat diet, thereby maintaining the efficient processing of FAs by astrocytes [58].

Butyrate plays a crucial role in promoting fatty acid oxidation. In the presence of succinate and ketone bodies, butyrate significantly increases respiratory state 3 [1, 59]. This enhances the efficiency of mitochondria and makes it more challenging to produce reactive oxygen species (ROS). Furthermore, butyrate is converted to butyryl-CoA through acyl-CoA synthetase short-chain family member 2 (ACSS2), which antagonizes the binding of the metabolic intermediate (MCoA) to inhibit CPT1A, upregulates CPT1A activity, and promotes fatty acid oxidation [60]. When the butyrate pathway is impaired, hippocampal mitochondrial function can be compromised through HDAC4, leading to the downregulation of synaptic proteins [61] Butyrate sodium is the sodium salt form of endogenous butyrate, which is formed by the fermentation of dietary fibers by probiotics in the colon. It exerts anti-inflammatory effects in the brain by inhibiting the production of MCP-1, IL-1β, and CXCL10 [62, 63]. Additionally, the inhibitory effect of butyrate on brain inflammation shows gender differences, with butyrate exerting anti-inflammatory effects in female astrocytes but not in males [64].

Astrocytes have the capacity to uptake FAs that originate within the brain not only from the cerebrospinal fluid via the BBB but also from neighboring cells, including neurons and oligodendrocytes. In instances of heightened FAs accumulation within overactive neurons, lipoprotein ApoE-containing particles are conveyed out of the cells to astrocytes to avert lipotoxicity and are subsequently internalized by astrocytes [65]. This phenomenon could be ascribed to the elevated expression of genes in astrocytes in contrast to neurons [66]. Moreover, FAs absorbed by astrocytes undergo degradation to generate ATP and are subsequently excreted into the extracellular environment upon stimulation by glutamate released from neurons. This process triggers the activation of intermediary neurons, ultimately resulting in heightened synaptic inhibition. In the absence of astrocytes, neurons have a tendency to accumulate excessive FAs in LDs, which can result in lipotoxicity and mitochondrial dysfunction [67]. Astrocytes can also obtain FAs through the process of engulfing cellular debris within the brain.

However, when the ApoE4 gene, which is associated with AD, is expressed in the brain, the ability of astrocytes to effectively clear FAs is diminished, resulting in their accumulation. As a consequence, astrocytes become overwhelmed and can only reduce the uptake of FAs from neurons.Moreover, the ApoE genotype exerts an impact on neuronal lipid metabolism, as ApoE4 neurons demonstrate a reduced ability to generate LDs in comparison to ApoE3 neurons. Consequently, this leads to the accumulation of FAs within the cytoplasm, posing a potential threat to mitochondria [67].

Exogenous FAs have been identified as a prospective alternative carbon source for neurons in the management of CNS metabolic disorders [