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PreprintCited by 20Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsLipid metabolism and biosynthesis

APOE4/4 is linked to damaging lipid droplets in Alzheimer’s microglia

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Haney, Michael S., Pálovics, Róbert, Munson, Christy Nicole, Long, Chris, Johansson, Patrik, Yip, Oscar, Dong, Wentao, Rawat, Eshaan +20 more·2023·bioRxiv (Cold Spring Harbor Laboratory)
DOI 10.1101/2023.07.21.549930PMC PMC10401952
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Abstract

Several genetic risk factors for Alzheimer’s Disease (AD) implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells. However, the relationship between lipid metabolism in glia and AD pathology remains poorly understood. Through single-nucleus RNA-sequencing of AD brain tissue, we have identified a microglial state defined by the expression of the lipid droplet (LD) associated enzyme ACSL1 with ACSL1-positive microglia most abundant in AD patients with the APOE4/4 genotype. In human iPSC-derived microglia (iMG) fibrillar Aβ (fAβ) induces ACSL1 expression, triglyceride synthesis, and LD accumulation in an APOE-dependent manner. Additionally, conditioned media from LD-containing microglia leads to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for AD with microglial LD accumulation and neurotoxic microglial-derived factors, potentially providing novel therapeutic strategies for AD.

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  • LDAM have sustained activation, impaired phagocytosis and surveillance, and autophagy dysregulation.

    “Among these subsets, LDAM have been given much attention due to their sustained activation, impaired phagocytosis and surveillance, and autophagy dysregulation [26–28].”

    From HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV (2025) · cites this paper as [26]

    In “iMG upregulate ACSL1 and undergo TG lipid synthesis upon fAβ challenge” (page not provided), LD-high microglia show higher inflammatory-cytokine expression, lower homeostasis-marker expression, and dysfunctional phagocytosis. The Discussion (page not provided) links autophagy to lipid-droplet accumulation, but does not establish autophagy dysregulation as a measured LDAM trait. The paper also does not directly establish sustained activation or impaired surveillance. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Microglia near amyloid beta plaques accumulate lipid droplets in vivo.

    “More recent work has also shown that microglia near amyloid beta plaques accumulate LDs in vivo (Haney et al., 2023, Preprint; Prakash et al., 2023, Preprint).”

    From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Haney et al., 2023, Preprint

    In “Intracellular lipid accumulation is linked to AD pathology” (page unavailable), the paper reports lipid-positive cells near amyloid-beta plaques and, separately, lipid-droplet-positive microglia in mouse AD models. It suggests that the lipid-containing cells near plaques could be microglia, but says their cell type was not confirmed. The claim states that identification more definitively than this source supports. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Haney, M. S., Pálovics, R., Munson, C. N., Long, C., Johansson, P., Yip, O., Dong, W., Rawat, E., West, E., Schlachetzki, J. C., Tsai, A., Guldner, I. H., Lamichhane, B. S., Smith, A., Schaum, N., Calcuttawala, K., Shin, A., Wang, Y.-H., Wang, C., Koutsodendris, N., Serrano, G. E., Beach, T. G., Reiman, E. M., Glass, C. K., Abu-Remaileh, M., Enejder, A., Huang, Y., & Wyss-Coray, T.
Affiliations
  • Stanford Medicine (US)
  • Stanford University (US)
  • Gladstone Institutes (US)
  • University of California San Diego (US)
  • Banner Sun Health Research Institute (US)
  • Banner Alzheimer’s Institute (US)
  • University of California, San Francisco (US)
ORCID
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2023-07-25
DOI
10.1101/2023.07.21.549930
PMC
PMC10401952
OpenAlex
W4385237937
Cited by
20
References
58
Citations by year
2026: 2 · 2025: 6 · 2024: 11 · 2023: 1
Type
posted content
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Michael J. Fox Foundation for Parkinson's Research (U24 NS072026, 05-901, 211002, P30 AG19610)
  • Pew Charitable Trusts
  • Alexander and Margaret Stewart Trust
  • Arizona Department of Health Services (P30 AG19610, U24 NS072026, 05-901, 211002, Contract 211002)
  • Arizona Biomedical Research Commission (P30 AG19610, 05–901, Contracts 4001, 0011, 05‐901 and 1001, U24 NS072026, 4001, 0011, 05-901, and 1001, 211002)
  • National Institute on Aging (211002, P30-AG-19610, T32AG066596, AG-19610, RF1AG064928, AG066515, P30AG019610, 05-901, R03AG071791, AG069453, P30AG062429, P30AG059307, P30AG072980, P30AG066515, R01AG069453, P01AG073082, T32AG000266)
  • National Institute of Neurological Disorders and Stroke (NS072026, 211002, U24NS072026, 05-901, U24 NS072026 National Brain, P30 AG19610)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
Alzheimer's disease, APOE ε4, lipid droplets, microglia, ACSL1, lipid metabolism, amyloid-beta, fibrillar amyloid-beta, triglyceride synthesis, tau phosphorylation, neurotoxicity, iPSC-derived microglia, single-nucleus RNA sequencing, genetic risk factors

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