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

Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.

Immunity 57, 2651-2668.e12 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Alzheimer’s Disease ; Apoe ; Inflammation ; Lipids ; Microglia; Amyloid-beta; Alpha-synuclein; Apoe; Trem2; Mice; Neurodegeneration; Metabolism; Deposition; Expression; Peptide
ISSN (print) / ISBN 1074-7613
e-ISSN 1097-4180
Zeitschrift Immunity
Quellenangaben Band: 57, Heft: 11, Seiten: 2651-2668.e12 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Mass.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Developmental Genetics (IDG)
Förderungen Japan Society for the Promotion of Science (JSPS)
Chan Zuckerberg Initiative
ERC
Alzheimer Forderungs Initiative
Adelson Medical Research Foundation
Klaus Faber Stiftung
Uehara Memorial Foundation
German Research Foundation