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

Author

Listed:
  • Michael S. Haney

    (Stanford University School of Medicine
    Stanford University)

  • Róbert Pálovics

    (Stanford University School of Medicine
    Stanford University)

  • Christy Nicole Munson

    (Stanford University School of Medicine
    Stanford University)

  • Chris Long

    (Stanford University School of Medicine)

  • Patrik K. Johansson

    (Stanford University School of Medicine)

  • Oscar Yip

    (Gladstone Institutes)

  • Wentao Dong

    (Stanford University)

  • Eshaan Rawat

    (Stanford University)

  • Elizabeth West

    (University of California, San Diego)

  • Johannes C. M. Schlachetzki

    (University of California, San Diego)

  • Andy Tsai

    (Stanford University School of Medicine
    Stanford University)

  • Ian Hunter Guldner

    (Stanford University School of Medicine
    Stanford University)

  • Bhawika S. Lamichhane

    (Stanford University School of Medicine
    Stanford University)

  • Amanda Smith

    (Stanford University School of Medicine
    Stanford University)

  • Nicholas Schaum

    (Stanford University School of Medicine
    Stanford University)

  • Kruti Calcuttawala

    (Stanford University School of Medicine
    Stanford University)

  • Andrew Shin

    (Stanford University School of Medicine
    Stanford University)

  • Yung-Hua Wang

    (Gladstone Institutes)

  • Chengzhong Wang

    (Gladstone Institutes)

  • Nicole Koutsodendris

    (Gladstone Institutes
    University of California)

  • Geidy E. Serrano

    (Banner Sun Health Research Institute)

  • Thomas G. Beach

    (Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium)

  • Eric M. Reiman

    (Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium)

  • Christopher K. Glass

    (University of California)

  • Monther Abu-Remaileh

    (Stanford University)

  • Annika Enejder

    (Stanford University School of Medicine)

  • Yadong Huang

    (Gladstone Institutes
    University of California
    University of California
    University of California)

  • Tony Wyss-Coray

    (Stanford University School of Medicine
    Stanford University
    Stanford University)

Abstract

Several genetic risk factors for Alzheimer’s disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer’s disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer’s disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer’s disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer’s disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer’s disease.

Suggested Citation

  • Michael S. Haney & Róbert Pálovics & Christy Nicole Munson & Chris Long & Patrik K. Johansson & Oscar Yip & Wentao Dong & Eshaan Rawat & Elizabeth West & Johannes C. M. Schlachetzki & Andy Tsai & Ian , 2024. "APOE4/4 is linked to damaging lipid droplets in Alzheimer’s disease microglia," Nature, Nature, vol. 628(8006), pages 154-161, April.
    • Handle: RePEc:nat:nature:v:628:y:2024:i:8006:d:10.1038_s41586-024-07185-7
    DOI: 10.1038/s41586-024-07185-7
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