Upstream lipid and metabolic systems are potential causes of Alzheimer’s disease, Parkinson’s disease and dementias

Abstract

Brain health requires circuits, cells and molecular pathways to adapt when challenged and to promptly reset once the challenge has resolved. Neurodegeneration occurs when adaptability becomes confined, causing challenges to overwhelm neural circuitry. Studies of rare and common neurodegenerative diseases suggest that the accumulation of lipids can compromise circuit adaptability. Using microglia as an example, we review data that suggests increased lipid concentrations cause dysfunctional inflammatory responses to immune challenges, leading to Alzheimer’s disease, Parkinson’s disease and dementia. We highlight current approaches to treat lipid metabolic and clearance pathways and identify knowledge gaps towards restoring adaptive homeostasis in individuals who are at-risk of losing cognition.

Graphical Abstract

Brain health requires circuits, cells and molecular pathways to adapt when challenged and to promptly reset once the challenge has resolved. Neurodegeneration occurs when this cycle of adaptability becomes confined, causing challenges to overwhelm neural circuitry. Here, we discuss how abnormal lipids compromise circuit adaptability through microglia, potentially causing Alzheimer’s disease, Parkinson’s disease and dementia.

Lipid diversity enables the adaptive homeostasis of the human brain

The term adaptive homeostasis describes the responsiveness of molecular pathways, cells and organs to maintain an individual’s health [1, 2]. A diverse repertoire of homeostatic responses can even be considered a hallmark of organismal health. In the case of the human brain, adaptive homeostasis coordinates several processes that include metabolism, vesicular trafficking, intercellular signals, synaptic plasticity and inflammation, which maintain the high functional thresholds of neuronal circuits controlling cognition and motor function [3]. When adaptive homeostasis fails, high functional threshold systems erode and vulnerable neuronal circuits degenerate (Figure 1).

Figure 1. Multiple challenges to cell type specific circuitry cause flux between functional states (healthy aging) or cumulative synaptic loss and circuit failure (neurodegeneration) at rates dependent upon the circuit’s lipid diversity and genomic sequence.

Healthy aging of the human brain is enabled by the adaptive homeostasis of neuronal circuits (green line). Periodic challenges to the integrity of vulnerable neuronal circuits, for example infections and acute toxicity, lead to transient synaptic loss. Metabolic reprogramming confers an adaptive reserve that supports the regrowth of synapses and the return of the circuit to adaptive homeostasis although cumulative hits reset the baseline circuit function. Rare neurodegenerative diseases cause a range of circuit dysfunction that is influenced by the strength of the genetic mutation, the vulnerability of the neuronal circuit and modified by lipid transport status (red line). Such a dominant strain on the neuronal circuit causes early onset failure. Common neurodegenerative diseases such as PD and AD withstand early challenges to circuit integrity but cumulative damage leads to an inability to return circuitry to a homeostatic rate (for example, in the case of unresolved neuroinflammation linked to lipid accumulation), leading to late-onset circuit failure (blue line, e.g. PD or AD).

Since lipids are the dominant structural component of the brain and each type of lipid is likely to have specific functions, parsimony suggests that the adaptive homeostasis of human brain circuits requires a tightly regulated and diverse lipidome. Consistent with this argument, the healthy human brain has two phases of lipid diversity. First, the range of lipid molecules increases from infancy to adulthood during a period that includes myelination and significant synaptic growth and plasticity [4]. Second, the developed lipid diversity is retained during healthy aging of the adult brain [4]. However, genetic mutations can cause specific lipids to accumulate, simplifying lipid diversity and leading to rare neurodegenerative diseases (Figure 1). The causes for more common neurodegenerative diseases remain unclear but emerging data links multiple challenges, such as neuroinflammatory events, to lipid accumulation and neurodegeneration [5–7]. Indeed, biochemistry has linked protein aggregation to lipid hydrocarbon chain length but the upstream intracellular causes of lipid changes and accumulation remain elusive [8]. Furthermore, patient analyses have used a range of brain regions to evaluate bulk lipid profiles during neurodegeneration but the results have been quite varied, indicating the importance of cellular resolution to evaluate lipid distribution processes between cell types in vulnerable brain regions (Table 1). Here we consider lipid diversity as an upstream regulator of adaptive homeostasis and inflammation in the human brain that is lost in Alzheimer’s disease (AD), Parkinson’s disease (PD) and dementias.

Table 1.

Analysis of published lipid profiles of brain tissue from FTD, PD and AD patients.

Disease (Reference)	Region	PE	LPE	PC	LPC	PS	PI	PA	CL	MAG	DAG	TAG	Chol	CE	SE	Cer	HexCer	GlcCer	GlcSph	SM	GM1	GM2	GM3	GD3	GD2	GD1	GT3	GT1	BMP
FTD GRN [63]	FL
FTD GRN [63]	OL
FTD GRN [64]	MFGC
PD [145]	SN
PD [146]	SN
PD [146]	Putamen
PD [147]	Putamen
PD [147]	Cerebellum
PD [148]	Caudate
PD [148]	GP
PD [148]	Putamen
PD [149]	ACG
PD [149]	Amygdala
PD [149]	Visual cortex
Early pathology, no dementia [150]	TL
Early AD [150]	TL
Mild AD (Braak stage 3–4) [151]	Cortex
Late AD [150]	TL
Severe AD (Braak stage 5–6) [151]	Cortex
AD [64]	MFGC
AD [152]	PFC
AD [152]	EC
AD APOE e2 [119]	RIPL
AD APOE e4 [119]	RIPL

Orange cells = significantly enriched lipid. grey cells = no significant change from healthy subjects. Green cells = significantly depleted. FL, frontal lobe, OL, occipital lobe, MFGC, mid frontal gyrus cortex, ACC, anterior cingulate cortex, SN, substantia nigra, GP, globus pallidus, TL, temporal lobe, EC, entorhinal cortex, PFC, prefrontal cortex, RIPL, right inferior parietal lobule.

Homeostatic cholesterol and sphingolipid metabolic pathways resolve initial inflammatory challenges without significant lipid accumulation or neurodegeneration

Thousands of different lipids form the human brain, cerebrospinal fluid and plasma and the concentration of these lipids changes during aging and disease [4, 9]. Different lipids regulate a range of organ functions from neuronal conductance to protein trafficking between subcellular compartments and receptor-mediated signal transduction [10, 11]. Although the human liver is a significant source of lipids, lipid transporters and related-regulatory signals for the entire body, the blood-brain barrier segregates circulating lipoprotein bound lipids from the brain, placing an emphasis on the brain to synthesize and tightly regulate the levels of its own range of lipids. Of particular interest for brain health are two groups of lipids: cholesterol and sphingolipids whose synthesis, utilization and clearance are linked to adaptive homeostasis and cell type specific functions.

Different organs rely on characteristic combinations of biochemical pathways to synthesize cholesterol. The brain is cholesterol-rich but produces low levels of cholesterol (2% of the total cholesterol produced by the liver) via a modified Kandutsch-Russell (K-R) pathway while the liver mainly uses the Bloch pathway to produce cholesterol [12–14]. A constitutively active K-R pathway is proposed to maintain myelin and plasma membrane pools of cholesterol in the brain, leaving the microglial Bloch pathway to adapt during chronic inflammation to sense phagocytosed lipids by activating Liver X Receptor (LXR) target gene expression without producing cholesterol [12, 15, 16]. Once synthesized, human brain cholesterol has a half-life of up to five years depending upon the pool [17]. Cholesterol in the brain can be cleared to the blood either directly by reverse transport using glial apolipoprotein E (APOE) or after metabolic conversion to 24S-hydroxycholesterol predominantly by neuronal cytochrome P450 family 46 subfamily A group 1 (CYP46A1) enzyme activity [17]. In a similar manner to cholesterol, each brain cell type synthesizes and uses patterns of intracellular sphingolipids and these patterns can change with age [5, 18–21]. Microglia in particular alter the expression of enzymes that metabolize sphingolipids during different inflammatory states while not synthesizing cholesterol. Such inflammatory stimuli can include viral infections [6, 7, 22, 23]. Singular, weak inflammatory stimuli can be readily handled by the brain’s immune system and efficiently resolved, although brain structure may remain altered for several months [24]. However, multiple stimuli over a lifespan, perhaps due to repeated viral infections, combined with genetic or environmental factors that increase lipid concentrations may lead to early microglial senescence and neural dysfunction, especially since the population of human microglia renews slowly (Figure 1)[25–27].

Lipopolysaccharide (LPS) is broadly used as a strong microglial stimulant that increases the expression of both anabolic and catabolic sphingolipid enzymes, immune signals and the transient accumulation of lipid droplets, an adaptive reserve of energy to support a high metabolic state (Figure 1) [28–31]. LPS-stimulated microglia can upregulate a range of lipids that include sphingolipids, phosphatidylcholine, lysophosphatidylcholine, diacylglycerols and triacylglycerols [32]. Autofluorescent, dysfunctional microglia upregulate the expression of catabolic sphingolipid enzymes and lipid transfer proteins [33]. Aged microglia do not alter the expression of sphingolipid metabolic enzymes but upregulate the expression of both immune signals and lipid transfer proteins [34]. The cholesterol and sphingolipids produced by these synthetic pathways may also interact within the membranes of different cell types. For example, sphingolipids interact with cholesterol at the neuronal synapse and regulate Toll-like receptor activity at the phagocytic plasma membrane [35–39].

Lipid accumulation uncouples adaptive homeostasis, leading to aberrant neuroinflammation and the degeneration of vulnerable brain circuits.

Rare neurodegenerative diseases provide direct evidence that genetic mutations can cause lipids to accumulate, ending homeostatic control over neuroinflammation and leading to neurodegeneration. Niemann-Pick disease type C1 (NPC1) is primarily caused by loss-of-function genetic mutations in NPC1, which encodes an intracellular cholesterol transporter. NPC1 patients accumulate endolysosomal cholesterol and monosialotetrahexosyl (GM1) ganglioside across many organs but experience symptoms mainly due to brain and liver dysfunction, suggesting organ specific vulnerabilities to lipid accumulation. In the NPC1 patients’ brain, the age at onset of cognitive decline correlates with the extent of Lewy bodies (LBs) and neurofibrillary tangles (NFTs) [40, 41]. These data suggest that lipid accumulation is sufficient to cause the hallmarks of common neurodegenerative diseases even though NPC1 mutations are not associated with AD or PD. From the perspective of therapeutics, inhibiting brain cholesterol synthesis is not therapeutic. Statins are a clinically validated approach to lowering cholesterol levels by inhibiting the rate limiting enzyme for cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase, reducing the incidence of major vascular events [42]. While epidemiological links between statin use and neurodegeneration remain unclear, lipophilic statins that can readily enter the brain have been investigated as treatments for neurodegenerative disease. Recently, Lovastatin, which is a lipophilic statin, slowed the deterioration of ¹⁸F-dopa uptake but did not treat the clinical rating scale of 77 patients with early stage PD over two years [43]. Instead, preclinical studies in NPC1 have demonstrated neuron and oligodendrocyte contributions to neurodegeneration and clinical signals link APOE status to human disease severity, implicating cholesterol clearance as a rational therapeutic approach for neurodegenerative disease [44–46].

In a similar manner to NPC1, Gaucher’s disease (GD) is a rare disease that causes lipids to accumulate in the liver and brain. Instead of the cholesterol and GM1 accumulation observed in NPC1 patients, GD patients accumulate sphingolipids in myeloid cells (Gaucher cells, foamy macrophages). Two copies of glucosylceramidase beta 1 (GBA1) mutations cause GD, and a single copy increases the risk of developing PD and cognitive decline (Figure 2) [36, 47–50]. The lost sphingolipid diversity leads to neurodegeneration and neuroinflammation. In the brain tissue of PD patients, a loss of glucocerebrosidase activity is associated with an accumulation of insoluble alpha-synuclein [51] and triglyceride concentrations correlate with a potential biomarker of inflammation [52, 53]. The administration of a small molecule inhibitor of glucocerebrosidase to mice reproduces the findings in patients [54]. Similar increases in high molecular weight alpha-synuclein protein are found in the brains of patients with Sandhoff’s disease and transgenic mice [55, 56]. Enzyme replacement therapy has successfully treated GD patients but does not enter the human brain in meaningful quantities. Miglustat is an inhibitor of glucosylceramide synthase (GCS), which lowers glucosylceramide levels and is an approved treatment for GD, reducing the risk associated with the loss of glucocerebrosidase activity but with low brain penetrance. Miglustat also has limited approval for treating NPC1, targeting the sphingolipids that accumulate alongside cholesterol, stabilizing the disease in patients. Miglustat is administered to nearly all NPC1 patients, either on- or off-label. Venglustat is another small molecule inhibitor of GCS with improved brain penetrance but fails to improve the symptoms of PD patients (NCT02906020). An alternate modality considered for improving glucocerebrosidase activity in the brain is gene therapy. Preclinical studies demonstrate that increased neuronal expression of GBA1 using an adeno-associated virus can reduce the accumulation of alpha-synuclein [57, 58]. Similar approaches are being tested in patients (NCT04127578).

Figure 2. Multiple challenges to microglial function within cell type specific circuitry cause flux between functional states (healthy aging) or failure to support synapse health (neurodegeneration) at rates dependent upon the circuit’s lipid diversity and genomic sequence.

Healthy aging of the human brain is enabled by the adaptive homeostasis of microglia as a cellular component of brain circuitry (green line). Periodic immune challenges to the integrity of vulnerable neuronal circuits, for example viral infections, lead to transient dysfunctional synaptic surveillance and synaptic loss. Lipid droplets support the reprogramming of microglial metabolism to stabilize the neuronal circuitry and the return of the circuit to adaptive homeostasis although cumulative hits reset the baseline circuit function. Neuronopathic forms of GD are caused by 2 rare mutations in GBA that disrupt lipid metabolism and inflammation (red line). Such a dominant strain on the neuronal circuit causes early onset failure. Idiopathic PD is influenced by lipid levels and genetic variation such as single copies of GBA mutations. Early challenges to microglial function are withstood but cumulative damage leads to an inability to return circuitry to a homeostatic rate (for example, in the case of unresolved neuroinflammation linked to lipid accumulation), leading to late-onset circuit failure (blue line, PD).

Frontotemporal lobar dementia (FTD) is another rare disease that is linked to dysfunctional neuroinflammation and lipid accumulation. As with GD, the number of genetic mutations in a specific gene causes different types of neurodegenerative disease. Homozygous mutations in granulin precursor (GRN) cause neuronal ceroid lipofuscinosis (NCL) in childhood while FTD can be caused by heterozygous GRN mutations and presents in adulthood. GRN FTD patients accumulate lipids in the brain and the cerebrospinal fluid (CSF) and serum contains inflammatory biomarkers [59–64]. Similar results linking lipid accumulation to inflammation have been observed in experimental models (Figure 3). Loss of Grn accelerates atherosclerosis and increases levels of polyunsaturated triacylglycerides [64, 65]. Microglia in mouse brains without Grn accumulate high levels of lipid droplets [29]. Brain aging and FTD are both marked by the accumulation of lipofuscin, a substance rich in lipids and proteins that is resistant to intracellular degradation in a manner similar to other pathological hallmarks of neurodegenerative disease. Indeed, lipofuscin levels can be used to discern young tissue from old tissue based on autofluorescence [66]. Lipofuscin accumulates in the neuronal subtypes that are vulnerable to degeneration in PD, AD and dementia, marks senescent cells, including microglia, is a pathological hallmark of NCL and GRN-FTD as well the brains of Grn knockout and aged mice [33, 67–71].

Figure 3. Molecular level influences of microglial lipids function.

(A) Microglia in a surveillance state (adaptive homeostasis) respond to a singular inflammatory challenge by upregulating lipid droplet synthesis that supports glycolysis (adaptive reserve), activated TREM2 at the plasma membrane leads to an upregulation of C1Q and APOE levels. APOE contributes to the clearance of excess microglial lipids. Lysosomal function is increased through NPC1, GRN and GBA. The increased presence of lipids is detected by astrocytic GPNMB. The inflammatory status of the microglia is efficiently stopped by APOE interactions with C1Q and metabolism returns to a homeostatic state (OXPHOS). (B) In response to sequential inflammatory stimuli, increased lipid levels and genomic sequence changes, microglia are slower to end the inflammatory state, leading to an acquired lipid profile dependent upon the combination of age, challenge, lipid levels and genomic risk. Created with Biorender.com.

In addition to lipid accumulation, the expression of Triggering receptor expressed on myeloid cells 2 (Trem2) and complement pathway components are upregulated in the brains of mice lacking either Npc1 or Grn, functionally linking lipid accumulation to neuroinflammation [64]. Therapeutic strategies to increase progranulin levels (the protein encoded by GRN) in at-risk individuals and FTD patients are being evaluated. Progranulin protein engineered for improved brain distribution can improve sphingolipid levels, lipofuscin levels, lysosomal function and inflammation in mice lacking Grn [72]. Clinical studies of the engineered progranulin protein have now started (NCT05262023). A different approach uses monoclonal antibodies raised against sortilin, a progranulin-interacting protein, to upregulate progranulin levels in preclinical models [73]. A monoclonal antibody raised against sortilin is under investigation to increase progranulin levels in individuals carrying heterozygous GRN mutations (NCT04374136). A third approach for progranulin proposes to use gene therapy to drive the expression of GRN. Preclinical studies of gene therapy using an adeno-associated virus to express Grn have shown reduced lipofuscin levels and improved lysosomal biochemistry in mice lacking Grn although the novel protein was immunogenic [74, 75]. Gene therapy for GRN is now being evaluated in early symptomatic FTD patients with GRN mutations (NCT04747431).

Lipid clearance supports adaptive homeostasis, limiting inflammation and maintaining brain health

Lipid removal pathways strongly influence the pathobiology of cognitive decline in patients and represent a rational group of therapeutic targets. While the concentrations of cholesterol in the cerebrospinal fluid remain unclear, increased plasma concentrations of cholesterol are found in patients with AD and related dementia, PD and amyotrophic lateral sclerosis (ALS) [76–83]. In addition to plasma concentrations of cholesterol, other lipid profiles are linked to common neurodegenerative diseases. Lipid levels in AD patient brains correlate with the extent of neurofibrillary tangles and the genomic signatures of AD are enriched in the enhancers of microglia, linking inflammation to lipids and cognitive decline [84, 85]. With respect to PD, neuromelanin colocalizes with cholesterol in healthy aged brains but PD patients have less nigral cholesterol and lipid droplets become associated with alpha-synuclein fibrils in a process consistent with protein fibrillization in other melanized lysosome-related organelles [52, 86–88].

When lipids accumulate within the cell, several mechanisms are employed to clear and transport the lipids for recycling or excretion. LXRs are nuclear receptors that form heterodimers with retinoid X receptors (RXRs) and activate target gene expression to remove intracellular lipids [89]. LXR/RXR activation can increase the expression of ATP binding cassette subfamily A member 1 (ABCA1), subfamily 6 (ABCG1) and APOE to reduce intracellular lipid concentrations [90, 91]. ABCA1 and ABCG1 are cholesterol transporters that work together to transfer cellular cholesterol to apolipoprotein A-1 and form extracellular high-density lipoprotein [92–95]. Recently generated structures of ABCG1 suggest that sphingomyelin may contribute to the cholesterol efflux by ABCG1 at the membrane [96]. In addition to lipid clearance, LXR, RXR and peroxisome proliferator-activated receptor (PPAR) complexes can regulate Complement Component 1q (C1q) expression and block inflammatory gene expression, directly linking intracellular lipid levels to inflammation [97]. From the perspective of therapeutics, Bexarotene is an RXR agonist that works with ApoE to remove intracellular lipids and clear soluble amyloid beta from mouse models of Alzheimer’s disease and improve memory and cognition [98]. However in the clinic, Bexarotene may reduce brain amyloid in patients with moderate AD without APOE e4 alleles but did not improve patient symptoms and the increased circulating levels of triglycerides posed a risk for cardiovascular disease in the patients (NCT01782742) [99]. It remains unclear whether Bexarotene is sufficiently beneficial to warrant continued investigation in the clinic.

Of these LXR targets, APOE levels appear to be a particularly important link between lipids, inflammation and neurodegeneration (Figure 3). Consistent with clinical data linking lipids and inflammation to neurodegenerative disease, APOE is an intercellular lipid transporter whose genomic sequence variation influences the onset and progression of cognitive decline in dementias, PD and NPC1 [49, 50, 100–106]. Recent data demonstrates that sequence variation in GBA further accelerates cognitive decline in PD patients carrying at least one copy of the APOE disease allele, inferring a significant consequence of concomitant sphingolipid and cholesterol accumulation in the human brain [103].

The molecular mechanisms of APOE-mediated risk of neurodegeneration remain unclear. APOE is produced by multiple cell types in the body, including the brain, liver, blood and vasculature and incorporates into lipoprotein particles that are composed of varying concentrations of cholesterol, triglycerides, proteins and other lipids. The liver uses receptor-mediated uptake of APOE to maintain organismal health by collecting lipids from the blood for metabolism and excretion through the biliary system. However, the mechanism of lipid clearance from the brain has been difficult to demonstrate. Data suggests that the pools of APOE in the plasma and cerebrospinal fluid are not functionally linked during neurodegeneration and liver-derived APOE does not cross the blood-brain barrier [107–110]. However, plasma APOE levels and glucose concentrations in the brain are correlated, suggesting other signals cross the blood-brain barrier to support brain health [109, 111]. These data become important when considering that brain glucose metabolism is reduced before patients’ present with symptoms of dementia, suggesting an indirect influence of plasma APOE on risk of neurodegenerative disease [112–116]. Furthermore, the strength of inflammatory challenges, such as COVID-19 infections (Figure 2), and lipid concentrations in the brain are linked to APOE status, underlining the importance of the linkage between lipids and inflammation for human health [117–119].

In the human brain, astrocytes express APOE to collect and transport locally produced lipids. APOE expression levels are also linked to immune activation and vulnerable populations of human neurons can upregulate APOE expression during early cognitive decline [120]. To examine the links between APOE levels and Tau pathology, a hallmark of AD and other dementias, translational studies have shown that transgenic overexpression of the low-density lipoprotein receptor (LDLR), the ApoE receptor, reduces ApoE concentrations in the cerebrospinal fluid, reduces Tau phosphorylation, and protects against hippocampal atrophy in a mouse model of tauopathy [121]. Furthermore, the study demonstrates the inverse relationship between ApoE and LDLR in microglial metabolism and myelin quality [121]. Reduced APOE function in human microglia leads to the accumulation of lipid droplets and neuronal network dysfunction in vitro [122]. The link between APOE and inflammation has been further investigated in the context of complement mediated inflammation. Complement activity in the brain regulates synaptic pruning and dysregulation is associated with cognitive decline [77, 123–126]. Increased lipid levels, whether from a high fat diet or loss of APOE function, upregulate interferon related gene expression in the mouse brain [84]. This neuroinflammatory signature can be reduced by inhibiting the downstream component of complement signaling, C5. Furthermore, APOE can bind to the upstream component of complement signaling, C1q and regulates the activity of classical complement pathway [84]. The expression of components of the complement signaling pathway are linked to the neuroprotective effect afforded by the neuroprotective APOE allele [127]. Indeed, efforts are underway to compensate for APOE e4 associated loss of lipid trafficking by overexpressing the protective APOE e2 variant using adeno-associated virus in the brains of at-risk individuals (NCT03634007), based on preclinical data that includes non-human primates [128].

Inflammatory signals link lipid accumulation to neurodegeneration

Other disease-associated inflammatory mechanisms are linked to lipid levels. Genome-wide association studies have linked glycoprotein nonmetastatic melanoma protein B (GPNMB) to a reduced risk of PD and more protein is found in PD-related regions of patient’s brains and plasma [53, 76, 129]. Interestingly, lipid accumulation rather than alpha-synuclein overexpression was sufficient to reproduce the patient’s biochemistry in mice, suggesting that GPNMB levels may report lipid levels in the brain [52, 53]. At the cellular level, microglia clear the brain of damaged synapses and dead cells. Infections and repetitive tissue damage cause microglia to activate beyond their homeostatic range, upregulate lipid droplets and fundamentally change metabolism and function before returning to their homeostatic range once the inflammatory trigger is resolved [6, 29, 130]. Repeated episodes of activation alter microglial function leading to altered gene expression patterns, the accumulation of lipofuscin, senescence, and myeloid recruitment of non-microglial cells to the brain, changing the immune status of the brain [29]. Furthermore, macrophages accumulate lipids in GD and NPC1, consistent with myeloid cell dysfunction linked to more common neurodegenerative diseases [131]. TREM2 is a receptor at the plasma membrane that is strongly expressed by myeloid cells, genomic sequence variation increases the risk of AD and can bind to apolipoproteins including APOE [132–134]. Deletion of TREM2 reduces the responsiveness of mouse microglia to extend beyond adaptive homeostasis, altering ApoE and lipoprotein lipase expression, and microglial cholesteryl esters and monosialodihexosylganglioside (GM3) accumulate [135–137]. Mice without either Trem2 or Grn also show reduced brain glucose metabolism, consistent with prodromal states of human neurodegenerative disease [138, 139]. Furthermore, a range of lipids can activate a nuclear factor of activated T cells (NFAT) reporter in vitro and the AD-associated risk allele, TREM2 R47H eliminates such lipid-related immune activity [140]. Similar TREM2 dependent changes in lipid metabolic genes are found in a population of mouse macrophages that expand in adipose tissue during a high fat diet [141]. As a therapeutic approach to stabilize TREM2, monoclonal antibodies against TREM2 can improve microglial activity and reduce plaque burden in preclinical models of AD although the potential therapeutic effects of the antibody on lipid metabolism remains unclear [142–144]. The efficacy and safety of a TREM2 antibody is currently being investigated in patients with early AD (NCT04592874).

Summary

In summary, we review the mechanisms of adaptive homeostasis linked to lipid metabolism and neurodegeneration. Genetics can clearly simplify lipid types and cause neurodegeneration. Our immediate challenge is to translate our findings from rare disease to common disease using genomic and environmental risks as a guide. The clearest example of this translational effort is GBA. Two copies of a GBA mutation are required to cause GD at an early age and one copy increases the risk of PD at a later age. Similar associations between gene copy number and the severity of neurodegenerative disease are found with APOE alleles. From the clinical perspective, biomarkers are needed to identify individuals who are at risk of neurodegeneration so that biochemical interventions can improve and maintain function for a lifetime.

Abbreviations

AD

Alzheimer’s disease

PD

Parkinson’s disease

K-R

Kandutsch-Russell

LXR

Liver X Receptor

APOE

Apolipoprotein E

CYP46A1

cytochrome P450 family 46 subfamily A group 1

LPS

lipopolysaccharide

NPC1

Niemann-Pick disease type C1

GM1

monosialotetrahexosylganglioside

LB

Lewy body

NFT

neurofibrillary tangle

HMG-CoA

3-hydroxy-3-methyl-glutaryl-coenzyme A

GD

Gaucher’s disease

GBA1

glucosylceramidase beta 1

GCS

glucosylceramide synthase

FTD

frontotemporal lobar dementia

GRN

granulin precursor

NCL

neuronal ceroid lipofuscinosis

CSF

cerebrospinal fluid

TREM2

Triggering receptor expressed on myeloid cells 2

ALS

amyotrophic lateral sclerosis

RXR

retinoid X receptors

ABCA1

ATP binding cassette subfamily A member 1

ABCG1

ATP binding cassette subfamily G member 1

PPAR

peroxisome proliferator-activated receptor

C1q

Complement Component 1q

LDLR

low density lipoprotein receptor

GPNMB

glycoprotein nonmetastatic melanoma protein B

NFAT

nuclear factor of activated T cells

GM3

monosialodihexosylganglioside