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

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 Hunter Guldner; Bhawika S Lamichhane; Amanda Smith; Nicholas Schaum; Kruti Calcuttawala; Andrew Shin; Yung-Hua Wang; Chengzhong Wang; Nicole Koutsodendris; Geidy E Serrano; Thomas G Beach; Eric M Reiman; Christopher K Glass; Monther Abu-Remaileh; Annika Enejder; Yadong Huang; Tony Wyss-Coray

doi:10.1038/s41586-024-07185-7

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

Nature. 2024 Apr;628(8006):154-161. doi: 10.1038/s41586-024-07185-7. Epub 2024 Mar 13.

Authors

Michael S Haney^#^{1

2}, Róbert Pálovics^#^{1

2}, Christy Nicole Munson^{1

2}, Chris Long³, Patrik K Johansson³, Oscar Yip⁴, Wentao Dong⁵, Eshaan Rawat⁵, Elizabeth West⁶, Johannes C M Schlachetzki⁶, Andy Tsai^{1

2}, Ian Hunter Guldner^{1

2}, Bhawika S Lamichhane^{1

2}, Amanda Smith^{1

2}, Nicholas Schaum^{1

2}, Kruti Calcuttawala^{1

2}, Andrew Shin^{1

2}, Yung-Hua Wang⁴, Chengzhong Wang⁴, Nicole Koutsodendris^{4

7}, Geidy E Serrano⁸, Thomas G Beach⁹, Eric M Reiman⁹, Christopher K Glass⁷, Monther Abu-Remaileh⁵, Annika Enejder³, Yadong Huang^{4

7

10

11}, Tony Wyss-Coray^{12

13

14}

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
² Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.
³ Department of Materials Science & Engineering Department, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
⁵ The Institute for Chemistry, Engineering & Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA, USA.
⁶ Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA.
⁷ Development and Stem Cell Biology Graduate Program, University of California, San Francisco, CA, USA.
⁸ Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
⁹ Banner Alzheimer's Institute and Arizona Alzheimer's Consortium, Phoenix, AZ, USA.
¹⁰ Biomedical Sciences Graduate Program, University of California, San Francisco, CA, USA.
¹¹ Department of Neurology, University of California, San Francisco, CA, USA.
¹² Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
¹³ Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA. [email protected].
¹⁴ The Phil and Penny Knight Initiative for Brain Resilience, Stanford University, Stanford, CA, USA. [email protected].

^# Contributed equally.

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.

MeSH terms

Alzheimer Disease* / genetics
Alzheimer Disease* / metabolism
Alzheimer Disease* / pathology
Amyloid beta-Peptides / metabolism
Animals
Apolipoprotein E4* / genetics
Apolipoprotein E4* / metabolism
Culture Media, Conditioned
Female
Genetic Predisposition to Disease
Humans
Induced Pluripotent Stem Cells / cytology
Lipid Droplets* / metabolism
Lipid Droplets* / pathology
Male
Mice
Microglia* / cytology
Microglia* / metabolism
Microglia* / pathology
Phosphorylation
Triglycerides
tau Proteins

Substances

Amyloid beta-Peptides
Apolipoprotein E4
ACSL1 protein, human
Triglycerides
tau Proteins
Culture Media, Conditioned

Abstract

MeSH terms

Substances

Grants and funding