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Astrocytic functions and lipid metabolism: Correlations and therapeutic targets in Alzheimer's disease and glioblastoma

Corresponding Author

Xu Zhang

[email protected]

orcid.org/0000-0001-8113-856X

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China, Shanghai, China

Correspondence

Xu Zhang, NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China. Shanghai-MOST Key Laboratory of Health and Disease Genomics, NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai 200237, China.

Email: [email protected]

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Rongrong Gao,

Rongrong Gao

Clinical Center for Biotherapy at Zhongshan Hospital, Fudan University, Shanghai, China

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Liuke Yang,

Liuke Yang

College of plant protection, Nanjing Agricultural University, Nanjing, China

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Youwei Zhu,

Youwei Zhu

Clinical Center of Bio-Therapy at Zhongshan Hospital & Institutes of Biomedical Sciences, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China

Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China

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Tiancheng Zhang,

Tiancheng Zhang

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Xiaorong Shen,

Xiaorong Shen

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Wenwen Gu,

Wenwen Gu

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Long Yang,

Long Yang

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Shenjie Peng,

Shenjie Peng

Fudan University, Shanghai, China

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Xu Zhang,

Corresponding Author

Xu Zhang

[email protected]

orcid.org/0000-0001-8113-856X

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

Correspondence

Email: [email protected]

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Rongrong Gao,

Rongrong Gao

Clinical Center for Biotherapy at Zhongshan Hospital, Fudan University, Shanghai, China

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Liuke Yang,

Liuke Yang

College of plant protection, Nanjing Agricultural University, Nanjing, China

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Youwei Zhu,

Youwei Zhu

Clinical Center of Bio-Therapy at Zhongshan Hospital & Institutes of Biomedical Sciences, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China

Shanghai Institute of Infectious Disease and Biosecurity, Fudan University, Shanghai, China

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Tiancheng Zhang,

Tiancheng Zhang

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Xiaorong Shen,

Xiaorong Shen

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Wenwen Gu,

Wenwen Gu

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Long Yang,

Long Yang

NHC Key Lab of Reproduction Regulation, Shanghai Engineering Research Center of Reproductive Health Drug and Devices,Shanghai Institute for Biomedical and Pharmaceutical Technologies, Shanghai, China

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Shenjie Peng,

Shenjie Peng

Fudan University, Shanghai, China

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First published: 08 April 2024

https://doi.org/10.1002/ctd2.287

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Abstract

Background

The brain is a central key organ of the body containing the second highest lipid content only after adipose tissue. Lipids as the main structural components of biological membranes play important roles in a vast number of biological processes within the brain such as energy homeostasis, material transport, signal transduction, neurogenesis and synaptogenesis, providing a balanced cellular environment required for proper functioning of brain cells. Lipids and their metabolism are of great physiological importance in view of the crucial roles of lipids in brain development and function. Astrocytes are the most abundant glial cells in the brain and involved in various processes including metabolic homeostasis, blood brain barrier maintenance, neuronal support and crosstalk.

Results

Disturbances in lipid metabolism and astrocytic functions may lead to pathological alterations associated with numerous neurological diseases like Alzheimer's disease (AD) recognised as the most frequent cause of dementia leading to major progressive memory and cognitive deficits as well as glioblastoma (GBM) known as the most aggressive malignant brain tumour with a poor prognosis.

Conclusions

Herein, we not only review the level and role of altered lipid metabolism in correlation with astrocytic function and astrocyte-neuron crosstalk in AD and GBM, but also discuss important lipid-related metabolites and proteins participating in possible mechanisms of pathologically dysregulated lipid metabolism, offering potential therapeutic targets in targeted molecular therapies for AD and GBM.

1 INTRODUCTION

The brain is a central and pivotal organ highly enriched in lipids (constituting 50–60% of brain dry weight),¹ the major biomacromolecules characterised with poor water solubility and good solubility in non-polar organic solvent, and is regarded with the second highest lipid content next to the adipose tissue.² Lipids are a class of fatty substances differing in overall structure, molecular weight, head group configuration, carbon–carbon bond formation and other factors, among which fatty acids (FAs), phospholipids (PLs), sphingolipids, sterol lipids and triglycerides (TGs) are the five main brain lipid classes,³ serving as basic structural components of biological membranes and participating in a broad variety of physiological events, including chemical energy generation and storage, substance transport, cellular signalling, neural differentiation, axonal regeneration, synaptogenesis, synaptic plasticity and brain development.^4-14

The brain consists of neurons and non-neuronal cells such as glial and vascular epithelial cells, of which astrocytes represent the most abundant glial cells.^{15, 16} Astrocytes mediate diverse biological activities under physiological conditions, including structural and energy support for neurons,^{17, 18} neuronal development and maintenance,^{19, 20} formation, function and plasticity of synapses,^{21, 22} modulation of synaptic transmission,²² metabolomic homeostasis²³ as well as integrity of the blood–brain barriers (BBBs)^{24, 25} which is a semipermeable membrane regulating solute exchange between blood and brain parenchyma to maintain CNS homeostasis and function and partially separating local lipid metabolism of the brain from that of the body.^25-33 Apart from the well-known enzymatic capacity of glycogenesis and glycolysis,^34-38 components of lipid metabolism also exists in astrocytes, providing membrane components for neurons and other glial cells^{39, 40} and playing fundamental roles in astrocyte function including membrane fluidity, energy generation and intercellular signalling. Emerging evidence has shown that astrocytic usage of lipids stored in droplets via mitochondrial β-oxidation fulfils crucial energy-providing and neuroprotective roles in the brain,^{18, 41} whereby disruption in lipid metabolism, structure and function of astrocytes may lead to pathogenic mechanisms underlying an array of neurological diseases (Figure 1).

Details are in the caption following the image — **FIGURE 1**
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Lipids and astrocytes in brain function and neurological disease pathogenesis.

2 MAIN CLASSES OF LIPIDS IN THE BRAIN

2.1 Fatty acids

As one of the most well-known lipid class, fatty acids (FAs), the essential monomeric components of all lipids, account for almost 20% of the energy source through oxidation, for which astrocytes as the major provider of FA β-oxidation may be the essential place.^42-44 Additionally, FAs can also be utilised by astrocytes for producing ketone bodies under particular conditions (e.g. ischemia), serving as a substrate for neuronal energy production-related tricarboxylic acid (TCA) cycle.⁴⁵ FAs permeate the BBB through passive mechanisms, such as dissociation from albumin carriers, binding to the luminal membrane which belongs to endothelial cells, ATP-independent release and entrance into the cytosol. Additionally, they can traverse the BBB via protein-mediated transport, involving FA transport proteins (FATPs), FA translocase/CD36 (FAT/CD36), FA binding proteins (FABPs) and caveolin-1.^{46, 47} FAs can be further divided into unsaturated and saturated FAs (SFAs), from which the former subclass contains monounsaturated FAs (MUFAs) and polyunsaturated FAs (PUFAs), while the latter comprises palmitic acid, stearic acid and others.^{48, 49} PUFAs are highly enriched in the brain, with threefold to fourfold level over other tissues.^{50, 51} What is more, essential PUFAs play key roles in brain activity and development,^{52, 53} in which the ω−3 docosahexaenoic acid (DHA) are particularly involved in synaptogenesis, neurogenesis and neuroprotection in the brain.^54-57

2.2 Phospholipids

As the most abundant component of major categories of membrane lipids,^{58, 59} phospholipids (PLs) generally consist of two hydrophobic tails of FAs differing in length and a backbone-attached hydrophilic phosphate group.^60-62 PLs, which are synthesised in the mitochondria and endoplasmic reticulum (ER) tracing from diacylglycerol and phosphatidic acid (PA), spontaneously aggregate into the formation of bimolecular layers in aqueous environments on account of configuration and amphipathic propertys.⁶³ PLs can be classified into glycerophospholipids and phosphosphingolipids, of which glycerophospholipids are the prominent glycerol-based class of lipid molecules which can be further subclassified into subtypes such as PA, phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG), phosphatidylinositol (PI) and phosphatidylserine (PS) on the basis of variation in hydrophilic head groups and participate in a variety of physiological activities in the brain.^{59, 64, 65} Moreover, fates of brain cells are influenced by exposure to different PLs, such as differentiation of neural cells into astrocytes was promoted and inhibited with PE and PC treatment, respectively.⁶⁶

2.3 Sphingolipids

Sphingolipids containing sphingoid bases (also known as long-chain bases) and a set of aliphatic amino alcohols that includes sphingosine are mainly synthesised in ER. Sphingolipids comprise a large group of lipid molecules through compounding with different functional groups, such as ceramide (functional group of single hydrogen atoms) and sphingomyelin (SM) (functional groups including phosphocholine) with regards to structural composition, functioning as building blocks of membranes (e.g. lipid rafts)⁶⁷ and playing fundamental roles in formation and regulation of synapse structure and function,⁶⁸ cell recognition, signal transmission and inflammatory regulation of astrocytes.^69-72 Besides, sphingolipid metabolites have also been discovered to exert regulatory roles in autophagy, cancer cell growth, response to DNA damage and inflammation.^73-75

2.4 Sterol lipids

Sterol lipids include numerous organic molecules, of which cholesterol with four hydrocarbon rings is the main part. Cholesterol can be synthesised in ER by all nucleated cells, while over 70% of total body cholesterol are provided by the diet,⁷⁶ namely the cholesterol absorbed in the gut transfers into the liver and then spreads through the body. What is noteworthy is that the brain, unlike other organs, makes its own cholesterol because of effective prevention of peripheral cholesterol exchange between brain tissue and plasma cholesterol-carrying lipoproteins by the BBB.^77-79 In brain tissue, de novo synthesis of cholesterol is mainly performed in astrocytes which are considered as the main cholesterol producer in the brains,⁸⁰ though the majority of sterol is synthesised in oligodendrocytes in developing brain and has an association with myelination⁸¹ and oligodendrocytes, besides, cholesterol can also be synthesised in many other cell typess.^82-84 Apart from de novo synthesis,⁸⁵ brain cells are able to acquire cholesterol from neighbouring cells through the absorption of cholesterol-laden lipoproteins (e.g. apolipoprotein E [ApoE]) in a receptor-mediated way,^{86, 87} in which lipoprotein synthesis for cholesterol transport occurs in astrocytes.⁸⁸ With abundant existence in myelin and lipid membranes,⁸¹ cholesterol fulfils vital roles in the brain, including BBB integrity, organisation of lipid rafts (discrete microdomains present in the external leaflet of plasma membrane), regulation of cell membrane flexibility (through interaction with neighbouring PLs) and localisation and activity of diverse membrane proteins (e.g. membrane receptor and transporter proteins), axonal guidance, formation and maintenance of synapses and dendrites, synaptic membrane-related fluidity and ion channel function, glucose transport, intracellular signalling and other important neuronal functions.^{84, 89-103}

2.5 Triglycerides

As the major form of FA deposition and the optimal form of FA triesters of glycerol, TGs are essential ingredients of glycerolipid synthesis by assembling with other glycerol moleculess.¹⁰⁴ TGs mainly generated in the adipose tissue and liver can reach other tissues with the package into lipoproteins containing a hydrophilic exterior and a hydrophobic lipid core, including chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), very-high-density lipoproteins and high-density lipoproteins (HDL) only which can cross the BBBs.^105-108 Additionally, APOE and apolipoprotein J, the most abundant apolipoproteins synthesised in astrocytes, serve as receptor ligands on HDL^109-111 and play fundamental roles in lipid metabolism-associated structural support, enzyme activity and substrate deliverys.^{110, 112-114}

3 ASTROCYTE-NEURON LIPID METABOLISM COUPLING

In humans, the brain representing, on average, merely 2% of total body weight consumes approximately and over 20% of energy substrates during quiet waking and diverse tasks, respectively,^{115, 116} which depends on relatively efficient metabolic coupling between astrocytes and neurons. Physiologically, astrocytes are considered primarily as glycolytic cells with a large enzymatic capacity for glycolysiss,^{115, 117, 118} whereas neurons are predominantly oxidative.^119-121 Besides the glucose metabolism in which astrocytes participate in the delivery of blood-derived glucose to neurons as an obligatory energy fuel, glycogen storage and activity-dependent l-lactate production as a metabolic substrate for neurons during aerobic glycolysis,^{115, 122-124} astrocytes-neuron coupling of lipid metabolism has also been suggested to occur as a response to neuronal activity in protection of neurons from lipotoxicity.^{125, 126} This is a mechanism proposing that l-lactate-derived de novo synthesis of free FAs (FFAs) in overstimulated neurons is triggered during astrocyte-neuron l-lactate shuttle, resulting in excess FFAs in association to lipotoxicity-related reactive oxygen species (ROS) and lipid peroxidation chain reaction,¹²⁷ peroxidised FAs with devastating effects¹²⁷ are then transferred from hyperactive neurons to astrocytes via APOE-positive lipid particles, where they are directly stored in lipid droplets (LDs)^{125, 126, 128} which are dynamic organelles possessing a core of neutral lipids (e.g. cholesterol esters [CEs] and triacylglycerides), influencing FA breakdown for energy production¹²⁹ and buffering excess FFAs to prevent lipid accumulation¹³⁰ as well as utilised as an energy substrate in β-oxidation¹²⁶ (Figure 2).

The dynamic interchange between astrocytes and neurons in lipid metabolism is essential for brain health, especially under stress or disease conditions. During neurodegenerative diseases or within the tumour microenvironment of glioblastoma (GBM), the lipid metabolism pathways in astrocytes undergo significant changes, impacting their ability to support neuronal survival.^131-134 These conditions often lead to an imbalance in lipid homeostasis, resulting in increased neuronal susceptibility to lipid-induced damage. The altered lipid metabolism in astrocytes can contribute to the progression of neurodegenerative diseases by failing to adequately buffer the neuronal lipid overload or by inefficiently utilising lipids for energy production, thereby exacerbating neuronal dysfunction and cell death.^{133, 135, 136} Moreover, the astrocytic responses to neuronal signals may be compromised, leading to reduced neuroprotective actions and enhanced vulnerability of neurons to metabolic stress.¹³⁵ In the context of disease, it is speculated that enhancing the astrocytic capacity to buffer and process FFAs might potentially mitigate neuronal damage and could lead to improved outcomes in neurodegenerative diseases and brain tumours.

4 PATHOLOGICAL LIPID ALTERATIONS AND LIPID-RELATED THERAPEUTIC TARGETS IN BRAIN DISEASES

4.1 Alzheimer's disease

With the worldwide increase in longevity, Alzheimer's disease (AD) has emerged as the most common form of senile dementia, rapidly evolving into a major health concern.^137-139 This devastating, irreversible neurodegenerative disease is clinically manifested through memory loss, neuropsychiatric abnormalities, cognitive impairment, behavioural deficits and a progressive decline in self-care capacity.^140-142 Pathologically, AD is characterise by the presence of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau protein.^143-145 Embedded within this pathological framework are several influential hypotheses that further elucidate the mechanisms underpinning AD. The amyloid cascade hypothesis, for instance, posits that the aggregation of Aβ plaques is the primary event triggering the neurodegenerative cascade in AD.^{146, 147} This hypothesis is bolstered by genetic, biochemical and pathological evidence indicating that mutations in genes involved in Aβ metabolism, such as the amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2), lead to familial forms of AD characterised by increased Aβ production or aggregation. According to this hypothesis, Aβ plaques disrupt cell-to-cell communication, incite immune cell activation leading to inflammation and culminate in neuronal death and brain atrophy.^146-150 Concurrently, the tau hypothesis centres on the intracellular accumulation of hyperphosphorylated tau protein, resulting in the formation of NFTs.^{151, 152} Tau, a protein integral to the stabilisation of microtubules in neurons, becomes pathologically phosphorylated in AD, losing its microtubule-binding capability and aggregating into NFTs.^151-156 This disrupts neuronal transport systems and precipitates cell death. The interplay between Aβ accumulation and tau pathology, with evidence suggesting Aβ accumulation may precede and promote tau pathology, signifies a potential interdependence in AD pathogenesis. Moreover, the neuroinflammation hypothesis has garnered attention, advocating that neuroinflammation is not merely a consequence but a driving force in AD pathology. Chronic activation of the brain cells, such as microglia and astrocytes, in response to Aβ and tau pathology, engenders sustained neuroinflammatory responses that contribute significantly to neuronal damage and the progression of AD.^{157, 158}

What is more, the accumulation of lipid granules in glia, besides notorious Aβ deposition and tau aggregates, was highlighted with the examination of Auguste Deter's brain (the first described AD patient), suggesting a possible involvement of perturbations of lipid metabolism in AD pathology.^{159, 160} Altered lipid metabolism has subsequently been identified as playing a significant role in the pathogenesis of AD.^161-170

Recent AD pathology-related lipidome studies have demonstrated changes in content of numerous lipids (Table 1). Substantial differences in FA levels were observed in AD brain tissues,^{171, 172} including a decrease in levels of DHA present in frontal cortex grey matter¹⁷³ and hippocampus¹⁷⁴ to which damage correlates with impaired learning and memory,¹⁷⁵ suggesting a dysregulation of FA metabolism and may potentially marking this neurodegenerative disease.¹⁷⁶ Cholesterol accumulation observed in senile plaques and influenced brain regions from AD patients¹⁷⁷ has been reported in association with region-specific synapse loss.¹⁷⁸ A causal relationship between hypercholesterolemia and dysfunctional cholinergic system, cognitive impairments and pathology of amyloid and tau protein has been also demonstrated,^{179, 180} further supporting important roles of disturbed cholesterol metabolism in AD. What is more, detection of elevated CEs was performed in lipid raft-like mitochondria-associated ER membranes (MAMs)¹⁸¹ of which hyperactivity leads to cholesterol retention and synapse loss and correlates with cognitive deficits¹⁸² and in which accumulated cleaved products of APP cause mitochondrial dysfunction, interruption of cellular lipid homeostasis and membrane lipid alterations generally observed in AD pathogenesis.^{183, 184} Mitochondrial dysfunction, accompanied with increased oxidative stress, in neurons induces a lipid transfer to nearby astrocytes in which LDs accumulate, in turn, mitochondrial dysfunction in glial cells can be caused by accumulation of peroxidated lipids and oxidative stress, contributing to neurodegenerative processes.^185-187 Growing evidence has supported nonnegligible roles of PLs and sphingolipids in AD pathogenesis and progression, with studies reporting that PLs and sphingolipids, together with acylglycerols, FAs and sterol lipids, present significant content changes in AD brain tissues.^{173, 188-194}

TABLE 1. Summary of lipid changes in AD.

Lipids			Tissue	Changes in AD	References
Fatty acids	Omega-3 fatty acids	DHA	Brain; CSF; circulation	↓	^195-199
			MFG	↑	¹⁹⁸
			FCx	↓	²⁰⁰
		EPA	Brain; circulation	↓	¹⁹⁹
		EPA	MFG	↓	¹⁹⁸
		DPA	Brain	↑	²⁰¹
		ALA	Plasma	↑	²⁰²
	Omega-6 fatty acids	AA	Brain; CSF	↑	^{196, 203, 204}
			MFG	↓	¹⁹⁸
			HPC	↓	²⁰⁵
		LA	Brain; plasma	↓	^{198, 206}
	Saturated fatty acids		Brain; CSF	↑	¹⁹⁵
	Eicosanoids	PG	Brain	↑	²⁰⁷
Phospholipids	PC	Total PC lipids	Brain	↓	²⁰⁸
		PC-EPA	CSF	↓	²⁰⁹
		PC-DHA	Plasma	↓	²¹⁰
		PC-EPA	Plasma	↓	²¹⁰
	PE	Total PE lipids	HPC	↓	²⁰⁵
		PE-SA	HPC	↓	²¹¹
		PE-OA	HPC	↓	²¹¹
		PE-AA	HPC	↓	²¹¹
		PE-DHA	HPC	↓	²¹¹
	PS	Total PS lipids	Occipital lobe; inferior parietal lobule	↓	²¹²
Sphingolipids	CM	Total CM lipids	Brain	↑	²¹³
Sphingolipids	SM	Total SM lipids	CSF	↓	²¹⁴
Triglycerides		Total TG lipids	Serum	↓	²¹⁵
Triglycerides		Polyunsaturated TG	Brain	↓	²¹⁶
Sterol lipids	Cholesterol		Brain	↓	²¹⁷
	Cholesterol precursors		Brain	↑	²¹⁷
	Total oxidised cholesterol		Brain	↑	s²¹⁸

Abbreviations: AA, arachidonic acid; ALA, alpha-linolenic acid; CM, ceramides; CSF, cerebral spinal fluid; DHA, docosahexaenoic acid; DPA, docosapentaenoic acid; EPA, eicosapentaenoic acid; FCx, frontal cortex; HPC, hippocampus; LA, linoleic acid; MFG, medial frontal gyrus; OA, oleic acid; PC, phosphatidylcholine; PG, prostaglandin; PE, phosphatidylethanolamine; PS, phosphatidylserine; SM, sphingomyelin; SA, stearic acid; TG, triglyceride; ↑, increased from control; ↓, decreased from control.

4.1.1 APOE in AD

In comparison with early-onset familial AD, late-onset AD (LOAD) accounts for approximately 95% of all AD cases,^{219, 220} in which genetic predisposition, after aging, plays major roles in the onset of AD. As the strongest risk factor for LOAD, APOE is the main lipoprotein in the brain and plays pivotal roles in brain lipid metabolism, membrane remodelling and neuronal growth and repairs.^221-225 APOE mainly produced by astrocytes is released into extracellular space where essential lipids (e.g. cholesterol) are delivered to neurons adopting APOE-bound cargo through APOE receptors expressed on the neuronal surfaces.²²¹ In addition to the capacities of Aβ binding and influencing Aβ aggregation and clearance,^{223, 226} APOE participates in indirect regulation of Aβ metabolism through interactions with receptors (e.g. LDL receptor-related protein 1 [LRP1]).^{225, 227-232} Critical and isoform-specific role of APOE has also been demonstrated in formation of intraparenchymal Aβ deposits in APP transgenic mice.^233-236 APOE exists with 3 different alleles namely APOEε2, APOEε3 and APOEε4, translating to three protein isoforms termed APOE2, APOE3 and APOE4, of which APOE4 present in approximately 14% of worldwide populations^{224, 237} is the most prevalent genetic risk factor for AD.^238-241 A single amino acid difference between APOE3 and APOE4 (Cys 112 Arg) brings about a conformational change influencing the binding to Aβ, lipids and apolipoprotein receptors.²⁴² APOEε2 considered as a protective genetic factor associated with reduced risk for AD and late age at onset^{238, 243} has been reported to orchestrate differences in lipidome and transcriptome profiles of postmortem AD brain.^{237, 244} Conversely, APOEε4 markedly elevates AD risk,^{238, 243} in which heterozygous and homozygous APOEε4 allele may increase AD risk by three and 12 times, respectively,²⁴² accelerates disease course and worsens brain pathology.^245-247 A correlation between APOE4 genotype and increased expression of Serpina3n, a gene expressed by astrocytes and considered as a strong marker of reactive and aged astrocytes in the brain,^{248, 249} has been reported with a possible contribution to the pathogenic role of APOE4 in AD.²⁵⁰ Higher APOE4 level in cerebral spinal fluid of AD patients compared with that of control individuals has been connected to accelerated Aβ oligomer accumulation.²⁵¹ APOE4 may retard Aβ clearance and favour Aβ deposition via binding to Aβ after specific fragmentation.^{224, 242} APOE4 was reported to trap ATP-binding cassette transporters A1 (ABACA1) (a regulator of APOE4 lapidation in protection from lipid-poor ApoE4 aggregation) in late rather than recycling endosomes and alter ABACA1 membrane trafficking in astrocytes, which might result in reduced Aβ degradation.²⁵² Insufficient Aβ clearance also affects accumulation in synaptic cleft, contributing to disruption of hippocampal long-term synaptic plasticity related to learning and memory abilities.²⁵³ APOE4 is internalised in APOE receptors such as LRP1 which is also a member of Aβ receptors including VLDL receptor and ApoE receptor 2 (APOER2).²²⁸ Additionally, APOE4-induced reduction of dendritic spine density in mice^{253, 254} is consistent with pathological changes (dendritic spine density reduction and synapse loss) observed in brain tissues from AD APOEε4 carriers.²⁵⁵ APOE4 causes widespread AD phenotypes-associated cellular and molecular alterations in brain cells derived from human induced pluripotent stem cells (iPSCs), among which increased Aβ secretion as well as impaired Aβ uptake and cholesterol accumulation occurred in neurons and astrocytes, respectively.²⁵⁶ Astrocytic lipid metabolism is influenced by APOE4,^{256, 257} in which increased FA unsaturation and LD accumulation were found in APOE4-expressing human iPSC-derived astrocytes, which can be restored to basal state through supplementation of culture medium with choline (a soluble PL precursor).²⁵⁷ Furthermore, APOE4 can also impair astrocyte-neuron coupling of FA metabolism via decreased FA sequestering in LDs, reduced LD transport efficiency and lowered FA oxidation, resulting in lipid accumulation in astrocytes and hippocampus, diminished abilities of astrocytes in neuronal lipid elimination and FA degradation, accelerated lipid dysregulation and increased AD risk.²⁵⁸

4.1.2 ACSBG1 and ACSL6 in AD

Cellular accumulation and activation of FAs either synthesised de novo or taken up from diets require the ATP-dependent reaction catalysed by acyl-CoA synthetases (ACSs), a family of enzymes initiating FA metabolism-related reactions through ligation to coenzyme A (CoA).²⁵⁹ ACS enzyme family contain various members differing in distribution and FA substrate preference,²⁶⁰ among which only two show specific enrichment in the brain, ACS bubblegum family member 1 (ACSBG1) and ACS long-chain family member 6 (ACSL6),^{261, 262} suggesting their potentially particular roles in modulation of brain FA metabolism. ACSBG1, almost exclusively expressed in astrocytes, have preferences for a wide range of substrates containing long-chain SFAs and unsaturated FAs.^{263, 264} ACSBG1 knockdown in vitro results in decreased ACS enzymatic activity and FA oxidation,²⁶⁴ indicating its participation in astrocytic FA oxidation, however, clear roles of ACSBG1 in brain function and/or dysfunction still remain poorly understood. ACSL6 showing high expression in the brain was reported to be downregulated in age-related neurodegenerative diseases^{265, 266} and in direct correlation with neurite outgrowths.^267-271 With high substrate preference for DHA of which low levels are associated with AD pathophysiology,²⁷² ACSL6 has been revealed with key roles in regulating DHA incorporation into neuronal membranes using Acsl6 deficient mice with significant reduction in DHA-containing PLs and impaired memory.^{273, 274} Critical roles of ACSL6 in brain DHA retention and neuroprotection are further supported by findings that ACSL6 depletion led to markedly reduced levels of brain membrane PL DHA, spatial memory deficits, hyperlocomotion, increased cholesterol biosynthesis and age-related neuroinflammation.²⁷⁵ What is noteworthy is that astrocyte-specific depletion had minimal influence on membrane lipid composition²⁷⁵ in consideration of ACSL6 enrichment in astrocytes,^{259, 276-280} possibly due to the expression of a DHA-non-preferring variant^{270, 281-286} and enrichment of Y-gate domain rather than DHA-preferring F-gate domain in astrocytes.²⁷⁰

4.1.3 ATAD3A in AD

ATPase family AAA-domain containing protein 3A (ATAD3A), a nuclear-encoded mitochondrial membrane-anchored protein belonging to the AAA+-ATPase protein family and simultaneously interacting with inner and outer mitochondrial membranes, is implicated in a variety of biological processes including stability maintenance of mitochondrial DNA, regulation of mitochondrial dynamics and cholesterol metabolism.^287-289 ATAD3A deficiency led to neurodegenerative phenotypes in association with cholesterol elevation, downregulated expression of cholesterol metabolism-related genes,²⁸⁸ optic atrophy and axonal neuropathy.²⁹⁰ Oligomerisation and accumulation of ATAD3A at MAMs, lipid raft-like ER subdomain rich in SM and cholesterol²⁹¹ and associated with diverse metabolic functions such as lipid metabolism, mitochondrial function and calcium homeostasiss,^292-296 have been discovered in both mouse models and postmortem human brain tissues of AD.²⁹⁷ Aberrantly oligomerised ATAD3A leads to cholesterol accumulation via expression inhibition of cholesterol clearance-mediating cytochrome P450 (CYP450) family 46 subfamily A member 1 (CYP46A1) located on MAMs of which deficiency correlates with cholesterol disturbance, amyloid aggregation and cognitive impairments,²⁹⁸ AD-like MAM hyperconnectivity (e.g. impaired MAM integrity)²⁹⁶ as well as synapse loss.²⁹⁷ MAM-resident cholesterol imbalance facilitates amyloidogenic APP cleavage,¹⁸⁴ in turn, retention of APP proteolytic fragments at MAMs interrupts cholesterol trafficking and homeostasis.²⁹⁹ Additionally, blocking ATAD3A oligomerisation by heterozygous knockout or pharmacological inhibition treated with DA1 peptide has been reported in causal relationship with cholesterol turnover normalisation, MAM integrity enhancement, APP processing suppression, synapse loss mitigation and ultimate reduction of AD-like neuropathology and cognitive impairments,²⁹⁷ further revealing a role of ATAD3A in AD pathology and suggesting a potential therapeutic strategy of retarding AD progression through manipulation of abnormal ATAD3A oligomerisation.

4.1.4 FoxO3 in AD

Forkhead box O transcription factor 3 (FoxO3) belonging to the forkhead box (FOX) family sharing an evolutionarily conserved forkhead DNA-binding domain composed of 80 to 100 amino acids³⁰⁰ and possessing single nucleotide polymorphisms (SNPs) associated with human longevity^{301, 302} functions as a mediator of biological processes promoting lifespan and preventing aging-related diseases,^{303, 304} of which alterations are involved in carcinoma, cardiovascular and neurodegenerative diseases.^{302, 305-308} FoxO3 plays a pivotal role in quiescence maintenance of neural stem cells (NSCs) in the brain, removal of which induces NSC differentiation and consequent NSC pool reduction.^309-312 Apart from capacities for neuronal survival promotion or neuronal apoptosis mediation,^{313, 314} FoxO3 has also been shown with astrocyte proliferation controlling through inhibiting inflammatory cytokines (e.g. TNF-α and IL-1β) mediating reactive astrogliosis in neurodegenerative diseases.^315-318 Conditional knockout of FoxO3 in astrocytes was reported to impair consumption of excess FAs³¹⁹ which are cytotoxic and destructive to mitochondrial function.³²⁰ FoxO3 reduction in aged mice was found to be specific to the cortex rather than the hippocampus, where FoxO3 deficiency caused cortical astrogliosis and dysregulated lipid metabolism.³¹⁹ In addition, lipid dysregulation, mitochondrial dysfunction together with Aβ uptake impairment were also observed in cultured astrocytes deficient in FoxO3, which could be reversed by astrocytic FoxO3 overexpression,³¹⁹ potentially supporting the concept that FoxO3 elevation in astrocytes may retard or restore cortical astrogliosis and AD-associated impairments.

4.1.5 GSAP in AD

Under typical conditions, Aβ peptides as the products of body's cholesterol disturbance are cleaved from APP which may occur in two cellular pools, namely lipid raft-associated pool preferentially favouring APP cleavage by β- and γ-secretase as well as non-raft pools where cleavage is performed by α-secretase in a non-amyloidogenic pathway³²¹ and rapidly eliminated to maintain normal Aβ levels.³²² γ-Secretase activating protein (GSAP) was first reported for its regulatory roles in γ-secretase activity and specificity and its significant and selective enhancement of Aβ production through interactions with γ-secretase and APP carboxy-terminal fragment (APP-CTF).³²³ Significantly upregulated GSAP level has been demonstrated in both AD mouse models and postmortem brain tissues from AD patients.^324-326 SNPs at the GSAP locus have been shown association with AD diagnosis,^{327, 328} of which one SNP was found to correlate with GSAP expression and AD risk.³²⁹ Genetic knockdown and pharmacological inhibition of GSAP suppress Aβ generation and deposition and tau phosphorylation in AD mouse models.^{323, 324, 330} Apart from the promotion of APP-CTF partitioning into Aβ production-favouring lipid rafts, GSAP has also been shown to be enriched in MAMs, an intracellular domain where amyloidogenic APP processing responsible for dysregulated lipid metabolism is performed.^{331, 332} GSAP depletion lowers APP-CTF accumulation in lipid rafts, reduces ER-mitochondrial contacts elevated in AD,^332-335 and alters lipid profiles in a direction opposite to AD pathogenesis (e.g. GSAP depletion-raised levels of PE and PI showing consistent reduction in human AD brain).^{329, 336} What is more, interactions between GSAP and multiple components related to ER-associated degradation regulating mitochondrial function through MAM and participating in AD pathogenesis have also been revealed, further supporting crucial roles of GSAP in attenuating AD-associated pathogenic process.

Through lipidomic analysis, a detailed and comprehensive profile of lipid alterations in AD is offered, shedding light on the disease's underlying mechanisms and highlighting potential targets for intervention. The identification of significant changes in various lipid species, such as FAs, cholesterol, PLs and sphingolipids, in AD brain tissues, demonstrates the extensive involvement of lipid dysregulation in the disease. Notably, the decrease in DHA levels and the accumulation of cholesterol underscore the impact of lipid metabolism on AD's progression, linking these alterations to key pathological features like Aβ plaque formation and synaptic loss. The critical roles of APOE, especially the APOEε4 allele, are also emphasised in AD's pathogenesis through its influence on lipid metabolism. The involvement of enzymes and proteins such as ACSs and ATAD3A illustrates the potential of targeting lipid metabolic pathways in AD therapy. Lipidomic platforms facilitate early disease detection through identifying biomarkers and aiding in the development of preventive and therapeutic strategies. The advancements in lipidomics offer promising avenues for improving AD understanding, enhancing early diagnosis and developing targeted therapies, underscoring the significance of lipid regulation in AD treatment approaches.

The discovery of novel drug targets, such as genetic factors like APOEε4 and enzymes involved in lipid metabolism disruptions (e.g. ACSBG1, ACSL6 and ATAD3A), opens avenues for targeted therapies that aim to modify disease progression or alleviate symptoms.^{176, 223, 337} These potential treatments, including those targeting the stabilisation of lipid homeostasis and mitochondrial function, present a promising strategy given the important roles of altered lipid metabolism in AD pathology (Table 2).^{338, 339} However, the development of effective treatments is complicated by AD's multifactorial nature, involving a complex interplay of genetic, molecular and environmental factors.³⁴⁰ The challenges extend to drug delivery, particularly across the BBB, and the variability in patient response due to genetic and phenotypic heterogeneity among AD patients.^{341, 342} Current therapies offer limited effectiveness, primarily providing symptomatic relief without significantly altering the disease course.³⁴³ Moreover, therapeutic interventions targeting the central nervous system often carry significant side effects, and the effectiveness of many potential therapies depends on early intervention, which is hampered by current limitations in early diagnosis.^{344, 345} Therefore, while the prospects for innovative treatments targeting specific molecular disruptions in AD are promising, overcoming the multifaceted challenges requires a comprehensive approach that integrates advances in genetics, molecular biology and pharmacology with improvements in diagnostic methodologies to enable timely therapeutic interventions.^{346, 347}

TABLE 2. Clinical stages of trials related to lipid metabolism in AD and GBM.

NCT number	Disease	Lipid	Status	Phases	Enrolment	Study type	URL
NCT05218018	AD	Triglyceride	Completed	Not applicable	30	Interventional	https://ClinicalTrials.gov/show/NCT05218018
NCT00303277	AD	Cholesterol	Completed	Phase 4	35	Interventional	https://ClinicalTrials.gov/show/NCT00303277
NCT02719327	AD	Eicosapentaenoic acid	Completed	Phase 2/Phase 3	131	Interventional	https://ClinicalTrials.gov/show/NCT02719327
NCT00053599	AD	Cholesterol	Completed	Phase 3	400	Interventional	https://ClinicalTrials.gov/show/NCT00053599
NCT00939822	AD	Cholesterol	Completed	Phase 2	88	Interventional	https://ClinicalTrials.gov/show/NCT00939822
NCT00486044	AD	Cholesterol	Completed	Phase 2	103	Interventional	https://ClinicalTrials.gov/show/NCT00486044
NCT00151502	AD	Cholesterol	Completed	Phase 3	600	Interventional	https://ClinicalTrials.gov/show/NCT00151502
NCT01142336	AD	Cholesterol	Completed	Phase 4	49	Interventional	https://ClinicalTrials.gov/show/NCT01142336
NCT02029573	GBM	Cholesterol	Completed	Phase 2	36	Interventional	https://ClinicalTrials.gov/show/NCT02029573

4.2 Glioblastoma

Glioma as a malignant primary brain tumour originating from astrocytes or other glial cells accounts for approximately 80% of all malignant brain tumours,³⁴⁸ of which GBM is the most aggressive type of brain tumour known with a 5-year survival rate below 5%.^349-351 Metabolic reprogramming has been recognised as a fundamental hallmark for carcinogenesis and progression of multiple tumours including GBMs,^352-354 through which tumour cells meet the high-energy demands of rapid proliferation.³⁵⁵ Except for the representative metabolic feature named the Warburg effect, a phenomenon in which GBM cells rely on glycolysis for energy production under oxygen-sufficient and oxygen-insufficient conditions,^{353, 355-357} GBM cells can also be fuelled by FA oxidation (FAO) as an alternative crucial energy resource to meet high-energy consumption in GBM aggressiveness,^358-362 of which inhibition negatively impacted GBM proliferation and progression.³⁶³

Oxidation of FAs is achieved by two major pathways, namely enzymatic oxidation mediated by peroxidases (e.g. cyclooxygenase, CYP450, lipoxygenase and phospholipase A2)³⁶⁴ as well as non-enzymatic self-catalysed peroxidation (Figure 3A) of which 4-hydroxynonenal (4-HNE) is an end-product showing elevated expression proportional to the grade of brain tumour malignancy.^365-367 Moreover, lipid metabolism reprogramming in association with numerous pathophysiological processes such as tumour proliferation and development^368-373 has been further evidenced with the observation of large amounts of LDs in GBM^374-376 and other tumours.^377-384 Neutral lipid core of a single LD includes cholesteryl esters and TGs composed of glycerol molecules with triple hydroxyl groups esterified by FAs.^385-388 TGs have been demonstrated to serve as an important energy reservoir for supporting GBM cell survival, in which LDs were rapidly broken down by GBM cells via autophagy, a pivotal cellular process degrading damaged organelles and protein aggregates and recycling nutrients via hydrolysis of cytoplasmic components to ultimately maintain cellular homeostasis,^389-392 to release stored FAs for producing energy upon energetic stress like glucose deprivation (Figure 3B), in turn, inhibition of FAO or autophagy led to LD retention and significant potentiation of GBM cell death,³⁹³ suggesting that LDs may play critical roles in regulating GBM growth and limitation of LD usage might be indispensable in GBM treatment. What is more, cholesterol metabolism in GBM is different from that in healthy brain tissues where nearly all brain cholesterol is synthesised de novo.^394-396 Contrary to normal astrocytes mainly synthesising cholesterol from glucose or glutamine^397-399 and converting excess cholesterol to oxysterol as an endogenous ligand of liver X receptors (LXRs) to consequently trigger efflux of surplus cholesterol via ABCA1 and suppression of cholesterol uptake by LDL receptors (LDLRs),^400-404 GBM cells are insufficient to de novo synthesise cholesterol and thus dependent on exogenously supplied cholesterol for survival through upregulated LDLR expression^{394, 405} (Figure 3C), in which LXR agonists could induce GBM cell death by lowering intracellular cholesterol content via ABCA1-dependent cholesterol efflux and LDLR inhibition.³⁹⁴ Additionally, intracellular cholesterol level has been revealed to be involved in resistance against GBM cell death induced by temozolomide (TMZ), a BBB penetrant chemotherapy agent currently used in the standard therapy for patients with GBM.^{406, 407} Furthermore, SMs, an important group of PLs in cell membranes, together with their hydrolysis by sphingomyelinases (SMase) are crucial to effects of radio- and chemotherapy.^408-411 Ceramides which are generated by SMase-mediated SM hydrolysis caused by TMZ and radiation can induce cell apoptosis,^412-414 which can be evaded through conversion of ceramides to sphingosine-1-phosphate (S1P) (Figure 4)^415-417 linked to tumour grade and implicated in GBM aggressive phenotypes.^{413, 418}

4.2.1 S1PRs in GBM

GBM cells utilise exogenous source of S1P synthesised and exported by astrocytes and neuronal cells⁴¹⁹ and endogenous S1P production⁴²⁰ for tumour progression. Involvement of S1P in tumour growth, migration, invasion, survival and angiogenesis^421-424 is specifically mediated by the family of G-protein coupled receptors named S1P receptors (S1PRs, S1PR1–S1PR5).^425-430 S1PR1, S1PR2, S1PR3 and S1PR5 are expressed in human GBM cells,^431-433 and elevated levels of S1PR1, S1PR2 and S1PR3 have been detected in brain tissues from GBM patients compared with healthy tissues, while only S1PR1 and S1PR2 showed significant association with GBM survival rates.^{431, 432} S1PRs are essential for mediating diverse S1P functions, whereas orientations in which they influence cell phenotypes still remain unclear. S1PR1 inhibition was reported to promote GBM cell proliferation, which collides with studies suggesting increased GBM proliferation by S1PR1–3, of which S1PR1 showed the strongest effects.^{432, 434} S1PR2 was shown to both reduce GBM migration through Rho/Rho kinase signalling pathway and participate in promoting GBM invasion.^{435, 436} In addition, S1PR5 has also been identified as an independent prognostic factor of GBM patients’ survival, aligning with reported role of S1PR5 in proliferation promotion.^{434, 437} Pharmacologically altered S1PR expression by fingolimod (FTY720), a sphingosine analogue leading to S1PR1 internalisation, has been revealed to suppress astrocyte activation and change astrocytic secretion of C-X-C motif chemokine 5 (CXCL5) known to promote GBM proliferation and migration.^438-440 Furthermore, functions of individual S1P receptor subtypes are dependent upon activation of diverse downstream effector proteins, especially coupling to different G-proteins,⁴²⁹ such as binding of S1PR1, S1PR2 and S1PR5 with Gi, activation of Gq by S1PR2 and S1PR3 as well as signalling of S1PR2, S1PR3 and S1PR5 via G12/13 (Figure 3),⁴⁴¹ which alters signalling of phospholipases (particularly phospholipase C (PLC) cleaving proximal phosphodiester bonds of glycerophospholipids in production of phosphorylated headgroups and diacylglycerols^{429, 430}) and further activates downstream signalling molecules (e.g. extracellular signal-regulated kinase, phosphoinositide 3-kinase and mitogen-activated protein kinase) (Table 3). What is noteworthy is that a S1PR-targeted liposomal drug delivery system, named S1P/JS-K/Lipo, capable of blood–brain tumour barrier penetration and enhanced tumour-targeted delivery has recently been described, efficiently delivering a nitric oxide prodrug (JS-K, O₂-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl) piperazin-1-yl] diazen-1-ium-1,2-diolate) to GBM tissues via specific interactions with S1PRs highly expressed on GBM cells,⁴⁴² representing a promising targeted approach for GBM therapy.

TABLE 3. Summary of S1PR-mediated effects in GBM.

Models	Involved S1PRs	Signalling pathways	Findings	References
LN18 GBM cells; U87MG GBM cells	S1PR1 ↑ S1PR2 ↑ S1PR3 ↑	PI3K/AKT1 pathway	Demonstrated association between S1P1 and S1P2 with GBM patient's survival. S1PR1/2 inhibition reduces GBM migration.	⁴⁴³
U373MG GBM cells	S1PR1 ↑ S1PR2 ↑ S1PR3 ↑	MAPK/ERK and PI3Kβ pathway	S1P promotes glioma cell proliferation.	⁴⁴⁴
U373MG GBM cells; GBM6 cells; GBM12 cells	S1PR2	MEK1/2 and Rho/ROCK	S1P induces mRNA and protein expression of PAI-1 and uPAR, which are important for GBM invasiveness.	⁴⁴⁵
U373MG GBM cells; U118MG GBM cells	S1PR1↑ S1PR2 S1PR3	MAPK-ERK Rho/ROCK	S1PR, S1PR2 and S1PR3 all positively contribute to S1P-stimulated glioma cell proliferation, of which S1PR1 makes the major contribution.	⁴⁴⁶
C6 glioma cells	S1PR2	MAPK/ERK, PKC, PLC, PLD and Ca²⁺ signalling	S1PRs are linked to at least two signalling pathways (i.e. PTX-sensitive Gi/Go–protein pathway and toxin-insensitive Gq/G11–PLC pathway).	⁴⁴⁷
C6 glioma cells; 1321-N1 astrocytoma cells	S1PR2	PI3K/Cdc42/p38MAPK and PI3K/Rac1/JNK	S1PR2 mediates S1P-induced negative regulation of glioma cell migration.	ADDIN⁴⁴⁸
U373MG GBM cells; U87MG GBM cells; M059K cells; U-1242 cells; A172 cells	S1PR1 ↑ S1PR2 ↑ S1PR3 ↑	MAPK/ERK and PI3K	S1P potently enhances glioma cell motility by signalling through coupling of S1PRs to Gi proteins.	⁴⁴⁹
T98G glioma cells; G112 glioma cells	S1P1, S1P2, S1P3 and S1P5	PTEN/AKT/Egr	S1PR1 is a significant prognostic factor for glioma. Downregulated S1PR1 expression increases glioma cell proliferation and enhances glioma malignancy.	⁴⁵⁰
Human GBM specimens; U87 glioma cells; U251 glioma cells; T98G glioma cells; G112 glioma cells	S1PR1↓		Downregulated S1PR1 expression in GBM patients with a poor survival. S1PR1 signalling negatively controls glioma cell proliferation.	⁴⁵¹

Abbreviations: AKT, v-akt murine thymoma viral oncogene homolog; Cdc42, cell division control protein 42 homolog; ERK, extracellular signal-regulated kinase; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase; PI3K, phosphoinositide 3-kinase; PLC, phospholipase C; PLD, phospholipase D; PTEN, phosphatase and tensin homolog; PTX, pertussis toxin; Rac1, Ras-related C3 botulinum toxin substrate 1; ROCK, Rho-associated protein kinase.

4.2.2 FABP7 in GBM

Fatty acid binding protein 7 (FABP7), a member of the multi-gene FABP family comprised of structurally related proteins with expression patterns specific to cell, tissue and development, binds to very-long-chain PUFAs such as DHA with high affinity.^{452, 453} FABP7 abundant in astrocytes^454-456 is a lipid chaperone mediating cellular uptake, intracellular trafficking and subsequent oxidation of FAs, whose expression was reported to be elevated in GBM and GBM stem-like cells forming neurospheres and might accounting for GBM aggressiveness^{457, 458} and recurrence as well as associated with proliferation, migration and invasion of GBM cells, GBM histology and reduced survival time.^459-464 Under metabolic stresses (e.g. hypoxia), FAs are stored as LDs and subsequently oxidised in a FABP-dependent manner for energy production in GBM cells.⁴⁶⁵ Slow-cycling cells (SCCs), a subpopulation of GBM cells preferentially utilising mitochondrial oxidative phosphorylation (OXPHOS), showing elevated lipid contents specifically metabolised under glucose deprivation and displaying enhanced capabilities of migration, invasion and chemoresistance, have been revealed with the characterisation of higher FABP expression and larger LD amounts in cultured conditions of normal oxygen levels or nutrients.⁴⁶⁶ Additionally, resistance of SCCs against deprived glucose or inhibited glycolysis could be restrained by FA uptake blocking via genetic deletion or pharmacological inhibition of FABP7.⁴⁶⁶ Moreover, promotion effects of FABP7 on GBM cell migration can be mitigated with DHA supplementation through specific and dramatic inhibition of DHA supplementation in culture medium on plasma membrane lipid order of FABP7-expressing GBM cells which positively correlates with GBM cell migration as well as DHA supplementation-mediated disruption of nanodomains formed by FABP7 on GBM cell membranes,⁴⁶⁷ further suggesting a critical role of FABP7 in lipid metabolism in GBM cells.

4.3 SCD in GBM

Stearoyl-CoA desaturase (SCD) is an ER-localised delta-9 FA desaturase forming carbon–carbon double bonds at the 9th to 10th position from the COOH-terminus of SFAs, stearic acid and palmitic acid and thus generating MUFAs, oleic acid and palmitoleic acid, respectively,^{468, 469} whose expression correlates with the ratio of MUFA to SFA in which a disequilibrium contributes to alterations in cell growth and differentiation.^468-471 SCD has 4 isoforms in mice (SCD1, SCD2, SCD3 and SCD4), while only two paralogs are expressed in human, namely SCD sharing approximately 85% amino acid identity with mouse SCDs and SCD5 unique to primates.^{470, 472} SCD has been described as a hypermethylated gene member contributing to the CpG island methylator phenotype which defines a distinct glioma subgroup.⁴⁷³ SCD expression in GBM, in contrast to SCD upregulation often observed in multiple human tumours,^474-477 was reported to be lower than normal brain tissues because of hypermethylation and monoallelic deletion together with phosphatase and tensin homolog frequently deleted in GBM⁴⁷⁸ in a subset of GBM patients.⁴⁷⁹ In addition, GBM cells without epigenetic and genetic changes mentioned above were revealed to express elevated SCD levels on which tumour cells rely for their survival.⁴⁷⁹ SCD inhibition by CAY10566, an inhibitor with a modest BBB penetration ability, has been demonstrated to not only significantly suppress intracranial GBM growth, but also obviously affect tumour vasculature including nearly complete blocking of intratumoural bleeding and possible normalisation of blood vessels, potentially allowing enhanced delivery of combinedly used antitumour drugs such as TMZ.⁴⁷⁹

The exploration of GBM lipid metabolism, through studies on FA oxidation, LDs accumulation and cholesterol metabolism alterations, suggests lipidomic analysis as a valuable tool for the early detection of GBM and the identification of new therapeutic targets. Markers like elevated 4-HNE levels and abundant LDs in GBM cells indicate tumour aggressiveness and highlight metabolic pathways ripe for intervention. GBM's reliance on external cholesterol sources, along with the important roles of proteins such as FABP7 and SCD, reveal exploitable metabolic vulnerabilities for developing treatment strategies (Table 2). Additionally, sphingolipids, especially S1P and its receptors, emerge as important components in tumour progression, serving both as biomarkers and potential therapeutic targets. Advancements in lipidomic platforms that allow for precise sphingolipid measurement might facilitate more effective GBM detection and therapy assessment.

5 CONCLUSIONS

The brain is highly enriched in lipids where they are crucial for multiple physiological processes ranging from maintenance of structural integrity and metabolic homeostasis to brain function and development. Metabolism of lipids is a complicated process in which a wide range of lipid-related effector proteins are involved and whose alteration is strongly associated with brain dysfunctions and diseases such as AD and GBM. In this review, we throw light upon basic classes of lipids including FAs, PLs, sphingolipids, sterol lipids and TGs, of which dysregulated metabolism can be regarded as disease biomarkers. We also briefly discuss the role of lipids within the brain and altered lipid profile correlated with astrocytic function and astrocyte-neuron crosstalk in AD and GBM. Moreover, we have discussed lipid-related metabolites and proteins critical for disease-associated lipid dyshomeostasis and how these proteins together with lipids in correlation with astrocytic functions modulate disease pathogenesis and development, enlightening their therapeutic potential in preventing onset and progression of AD and GBM. However, there are still several lipids whose association with AD and GBM and availability as clinically valuable biomarkers for disease detection at early stages need further evaluation, which can be performed by newly developed and improved techniques of gradually matured lipidomic platforms. What is more, there remains much to be discovered about benefits and risks of manipulation of compounds affecting effector proteins involved in lipid metabolism, and further characterisation of pathways in which important lipid-related proteins participate along with clinical studies will aid the understanding of pathogenesis mechanisms behind AD and GBM and identification of novel therapeutic targets to help ameliorate disease courses, facilitate disease treatments and consequently benefit patients.

AUTHOR CONTRIBUTIONS

X. Z. takes primary responsibility for the paper. X. Z. drafted the manuscript. R. R. G., Y. W. Z., L. K. Y., T. C. Z., X. R. S., W. W. G., L. Y. and S. J. P. participated in the literature search and manuscript writing. All the authors read and approved the final manuscript.

ACKNOWLEDGEMENTS

Not applicable.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflict of interest.

FUNDING INFORMATION

Not applicable.

ETHICS STATEMENT

Not applicable.

Open Research

DATA AVAILABILITY STATEMENT

Not applicable.

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Volume4, Issue2

April 2024

e287

Astrocytic functions and lipid metabolism: Correlations and therapeutic targets in Alzheimer's disease and glioblastoma