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

Kaji, Seiji; Berghoff, Stefan A.; Spieth, Lena; Schlaphoff, Lennart; Sasmita, Andrew O.; Vitale, Simona; Büschgens, Luca; Kedia, Shreeya; Zirngibl, Martin; Nazarenko, Taisiia; Damkou, Alkmini; Hosang, Leon; Depp, Constanze; Kamp, Frits; Scholz, Patricia; Ewers, David; Giera, Martin; Ischebeck, Till; Wurst, Wolfgang ; Wefers, Benedikt ; Schifferer, Martina ; Willem, Michael; Nave, Klaus-Armin; Haass, Christian ; Arzberger, Thomas; Jäkel, Sarah; Wirths, Oliver ; Saher, Gesine und Simons, Mikael (2024): Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis. In: Immunity, Bd. 57, Nr. 11: S. 2651-2668

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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Adolf-Butenandt-Institut ; Medizin > Munich Cluster for Systems Neurology (SyNergy) ; Medizin > Institut für Schlaganfall- und Demenzforschung (ISD) ; Medizin > Klinikum der LMU München > Neurologische Klinik und Poliklinik mit Friedrich-Baur-Institut ; Medizin > Klinikum der LMU München > Klinik und Poliklink für Psychiatrie und Psychotherapie
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1074-7613
• Bemerkung: Correction published online December 4, 2024
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198