Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis
The seeded growth of pathogenic protein aggregates underlies the pathogenesis of Alzheimer's disease (AD), but how this pathological cascade is initiated is not fully understood. Sporadic AD is linked genetically to apolipoprotein E (APOE) and other genes expressed in microglia related to immune, lipid, and endocytic functions. We generated a transgenic knockin mouse expressing HaloTag-tagged APOE and optimized experimental protocols for the biochemical purification of APOE, which enabled us to identify fibrillary aggregates of APOE in mice with amyloid-β (Aβ) amyloidosis and in human AD brain autopsies. These APOE aggregates that stained positive for β sheet-binding dyes triggered Aβ amyloidosis within the endo-lysosomal system of microglia, in a process influenced by microglial lipid metabolism and the JAK/STAT signaling pathway. Taking these observations together, we propose a model for the onset of Aβ amyloidosis in AD, suggesting that the endocytic uptake and aggregation of APOE by microglia can initiate Aβ plaque formation.
Authors
- Thomas Arzberger
- Alkmini Damkou (ORCID: https://orcid.org/0000-0002-5082-0790)
- Shreeya Kedia (ORCID: https://orcid.org/0000-0002-0445-1621)
- Patricia Scholz (ORCID: https://orcid.org/0000-0003-0761-9175)
- Benedikt Wefers (ORCID: https://orcid.org/0000-0002-2492-9389)
- Constanze Depp (ORCID: https://orcid.org/0000-0003-2868-6932)
- David Ewers (ORCID: https://orcid.org/0000-0003-1037-1027)
- Frits Kamp (ORCID: https://orcid.org/0000-0001-8382-6884)
- Martin Giera (ORCID: https://orcid.org/0000-0003-1684-1894)
- Wolfgang Wurst (ORCID: https://orcid.org/0000-0003-4422-7410)
- Michael Willem (ORCID: https://orcid.org/0000-0001-8829-3802)
- Luca Büschgens (ORCID: https://orcid.org/0009-0004-8833-2874)
- Susan Vitale (ORCID: https://orcid.org/0000-0002-5972-6848)
- Lennart Schlaphoff (ORCID: https://orcid.org/0000-0001-8043-4025)
- Klaus‐Armin Nave (ORCID: https://orcid.org/0000-0001-8724-9666)
- Andrew Octavian Sasmita (ORCID: https://orcid.org/0000-0001-7379-6749)
- Seiji Kaji (ORCID: https://orcid.org/0000-0001-7601-8897)
- Lena Spieth (ORCID: https://orcid.org/0000-0002-0308-0144)
- Martina Schifferer (ORCID: https://orcid.org/0000-0002-0500-8218)
- Oliver Wirths (ORCID: https://orcid.org/0000-0002-4115-0334)
- Stefan A. Berghoff (ORCID: https://orcid.org/0000-0002-3794-7295)
- Christian Haass (ORCID: https://orcid.org/0000-0002-4869-1627)
- Leon Hosang
- Gesine Saher (ORCID: https://orcid.org/0000-0003-3507-9604)
- Till Ischebeck (ORCID: https://orcid.org/0000-0003-0737-3822)
- Mikael Simons (ORCID: https://orcid.org/0000-0001-5329-192X)
- Martin Zirngibl (ORCID: https://orcid.org/0000-0003-4485-8423)
- Sarah Jäkel (ORCID: https://orcid.org/0000-0002-9634-2472)
- T. I. Nazarenko
Institutions
- Leiden University Medical Center (NL)
- German Center for Neurodegenerative Diseases (DE)
- Helmholtz Zentrum München (DE)
- Max Planck Institute for the Study of Religious and Ethnic Diversity (DE)
- Institute of Plant Biology and Biotechnology (KZ)
- Munich Cluster for Systems Neurology (DE)
- Hertie Foundation (DE)
- Max Planck Institute of Experimental Medicine (DE)
- Institute of Neuroimmunology of the Slovak Academy of Sciences (SK)
- University of Göttingen (DE)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Immunity
- Published
- 2024-10-16
- DOI
- https://doi.org/10.1016/j.immuni.2024.09.014
- Citations
- 77
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 25.15
Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Broad Institute
- Deutsche Forschungsgemeinschaft
- Japan Society for the Promotion of Science
- HORIZON EUROPE European Research Council