APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Lee, Sangderk; Devanney, Nicholas; Golden, Lesley R.; Smith, Cathryn T.; Schwartz, James L.; Walsh, Adeline E.; Clarke, Harrison A.; Goulding, Danielle S.; Allenger, Elizabeth J.; Morillo-Segovia, Gabriella; Friday, Cassi M.; Gorman, Amy A.; Hawkinson, Tara R.; MacLean, Steven M.; Williams, Holden C.; Sun, Runyuan; Morganti, Josh M.; Johnson, Lance A.

doi:10.1016/j.celrep.2023.112196

Cited by 65 publications

(59 citation statements)

References 121 publications

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“…In the context of APOE4, inhibiting triglyceride synthesis restores the expression of homeostatic genes and suppresses the activation of disease-associated genes, indicating that APOE4 cells have a pathological rewiring of lipid metabolism. This has been suggested in correlative data from other studies which show that APOE4 microglia have both a higher lipid burden and a more "activated" phenotype than APOE3 microglia 19,20,23,24 . Changes to triglyceride metabolism can also modulate essential microglial functions like phagocytosis and endocytosis of multiple substrates.…”

Section: Discussionmentioning

confidence: 59%

“…The APOE4 allele is associated with a 3fold (heterozygous) or a 12-fold (homozygous) increase in AD incidence 16 . As a lipid transport protein, APOE4 has been associated with the accumulation of cholesterol and triglycerides in several model systems 17,18,27,[19][20][21][22][23][24][25][26] . Our previous work identified that APOE4 increases triglyceride storage in lipid droplets in human induced pluripotent stem cell (iPSC)-derived astrocytes and microglia 22 .…”

Section: Introductionmentioning

confidence: 99%

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Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia

Stephenson,

Johnson,

Cheng

et al. 2024

Preprint

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Microglia modulate their cell state in response to various stimuli. Changes to cellular lipids often accompany shifts in microglial cell state, but the functional significance of these metabolic changes remains poorly understood. In human induced pluripotent stem cell-derived microglia, we observed that both extrinsic activation (by lipopolysaccharide treatment) and intrinsic triggers (the Alzheimers disease-associated APOE4 genotype) result in accumulation of triglyceride-rich lipid droplets. We demonstrate that lipid droplet accumulation is not simply concomitant with changes in cell state but rather necessary for microglial activation. We discovered that both triglyceride biosynthesis and catabolism are needed for the transcription and secretion of proinflammatory cytokines and chemokines in response to extrinsic stimuli. Additionally, we reveal that triglyceride biosynthesis and catabolism are necessary for the activation-associated phagocytosis of multiple substrates including the disease-associated amyloid-beta peptide. In microglia harboring the Alzheimers disease risk APOE4 genotype, triglyceride-rich lipid droplets accumulate even in the absence of any external stimuli. Inhibiting triglyceride biosynthesis in APOE4 microglia not only modifies the transcription of immune response genes but also attenuates disease-associated transcriptional states. This work establishes that triglyceride metabolism is necessary for microglia to respond to extrinsic activation. In APOE4 microglia, this metabolic process modulates both immune signaling and a disease-associated transcriptional state. Importantly, our work identifies metabolic pathways that can be used to tune microglial immunometabolism in APOE4-associated disease.

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Section: Discussionmentioning

confidence: 59%

Section: Introductionmentioning

confidence: 99%

Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia

Stephenson,

Johnson,

Cheng

et al. 2024

Preprint

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“…Accordingly, we observed changes to cholesterol homeostasis, adipogenesis, and hypoxia pathways in our APOE4-R47H glial cells. APOE4 is known to disrupt glial lipid metabolism and alter the balance between mitochondrial and glycolytic metabolism [101][102][103][104][105][106] . These metabolic effects of APOE4 are mediated by sex, with a stronger metabolic perturbation in APOE4 females 105,106 .…”

Section: Discussionmentioning

confidence: 99%

Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

Carling,

Fan,

Foxe

et al. 2024

Preprint

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The strongest risk factors for Alzheimer's disease (AD) include the ϵ4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk.

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“…On one hand, HIF1a promotes erythropoiesis, angiogenesis and exerts neuroprotection (Majmundar et al, 2010; Burtscher et al, 2021). On the other hand, there are contradictory reports on either the detrimental (Sun et al, 2006; March-Diaz et al, 2021; Lee et al, 2023) or protective (Ashok et al, 2017) role of HIF1a in neurodegeneration, Alzheimer’s disease in particular. To add the complexity, HIF1a is involved in inflammatory response and metabolism regulation (McGettrick and O’Neill, 2020; Taylor and Scholz, 2022).…”

Section: Supplementary Informationmentioning

confidence: 99%

Breakdown and repair of the aging brain metabolic system

Shichkova,

Coggan,

Kanari

et al. 2023

Preprint

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Cognitive impairments and neurodegeneration in aging are linked to disrupted brain energy metabolism. We address this experimentally challenging problem with a computational molecular model that provides mechanistic insights and therapeutic predictions. This model encompasses key enzymes, transporters, metabolites, and other important factors, enabling the investigation of over 66,000 molecular interactions within and across cellular and subcellular compartments of neurons, glia, and blood vessels. During aging, action potential generation is primarily impaired due to reduced expression of the Na+/K+-ATPase pump and diminished ATP supply. The metabolic system loses flexibility, hindering its ability to effectively respond to stimuli or adapt to molecular damage. Astrocytes may defer to neuronal energy stability at their own expense. We identified potential strategies for rejuvenating the aged brain including supplying nutritional factors to the blood, increasing the NADH cytosol-mitochondria shuttle capacity and the expression of Na+/K+-ATPase. Transcription factor analysis implicated the estrogen related receptor alpha (ESRRA) as having the highest potential impact on aging, suggesting that dysregulated energy metabolism may be a transitional state between healthy aging and neurodegenerative disorders, rather than a hallmark of aging. This high-fidelity model serves as a foundation for future research on aging and cognitive health.

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APOE modulates microglial immunometabolism in response to age, amyloid pathology, and inflammatory challenge

Cited by 65 publications

References 121 publications

Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia

Triglyceride metabolism controls inflammation andAPOE4-associated disease states in microglia

Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

Breakdown and repair of the aging brain metabolic system

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