Journal Article

DZNE-2025-00081

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.

Kaji, S.DZNE* ; Berghoff, S. A.DZNE* ; Spieth, L.DZNE* ; Schlaphoff, L.DZNE* ; Sasmita, A. O. ; Vitale, S.DZNE* ; Büschgens, L. ; Kedia, S.DZNE* ; Zirngibl, M.DZNE* ; Nazarenko, T.DZNE* ; Damkou, A.DZNE* ; Hosang, L. ; Depp, C. ; Kamp, F.DZNE* ; Scholz, P. ; Ewers, D. ; Giera, M. ; Ischebeck, T. ; Wurst, W.DZNE* ; Wefers, B.DZNE* ; Schifferer, M.DZNE* ; Willem, M. ; Nave, K.-A. ; Haass, C.DZNE* ; Arzberger, T.Extern* ; Jäkel, S. ; Wirths, O. ; Saher, G. ; Simons, M. (Last author)DZNE*

2024
Cell Press [Cambridge, Mass.]

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Please use a persistent id in citations: doi:10.1016/j.immuni.2024.09.014

Abstract: 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.

Keyword(s): Animals (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Microglia: metabolism (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Mice, Transgenic (MeSH) ; Amyloid beta-Peptides: metabolism (MeSH) ; Amyloidosis: metabolism (MeSH) ; Amyloidosis: pathology (MeSH) ; Amyloidosis: genetics (MeSH) ; Apolipoproteins E: metabolism (MeSH) ; Apolipoproteins E: genetics (MeSH) ; Signal Transduction (MeSH) ; Plaque, Amyloid: metabolism (MeSH) ; Plaque, Amyloid: pathology (MeSH) ; Brain: metabolism (MeSH) ; Brain: pathology (MeSH) ; Disease Models, Animal (MeSH) ; Lipid Metabolism (MeSH) ; Protein Aggregation, Pathological (MeSH) ; STAT Transcription Factors: metabolism (MeSH) ; Janus Kinases: metabolism (MeSH) ; Alzheimer’s disease ; ApoE ; inflammation ; lipids ; microglia ; Amyloid beta-Peptides ; Apolipoproteins E ; STAT Transcription Factors ; Janus Kinases

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Contributing Institute(s):

1. Molecular Neurobiology (AG Simons)
2. Genome Engineering (AG Wurst)
3. Neuronal Cell Biology (AG Misgeld)
4. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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