TY  - JOUR
AU  - Kaji, Seiji
AU  - Berghoff, Stefan A
AU  - Spieth, Lena
AU  - Schlaphoff, Lennart
AU  - Sasmita, Andrew O
AU  - Vitale, Simona
AU  - Büschgens, Luca
AU  - Kedia, Shreeya
AU  - Zirngibl, Martin
AU  - Nazarenko, Taisiia
AU  - Damkou, Alkmini
AU  - Hosang, Leon
AU  - Depp, Constanze
AU  - Kamp, Frits
AU  - Scholz, Patricia
AU  - Ewers, David
AU  - Giera, Martin
AU  - Ischebeck, Till
AU  - Wurst, Wolfgang
AU  - Wefers, Benedikt
AU  - Schifferer, Martina
AU  - Willem, Michael
AU  - Nave, Klaus-Armin
AU  - Haass, Christian
AU  - Arzberger, Thomas
AU  - Jäkel, Sarah
AU  - Wirths, Oliver
AU  - Saher, Gesine
AU  - Simons, Mikael
TI  - Apolipoprotein E aggregation in microglia initiates Alzheimer's disease pathology by seeding β-amyloidosis.
JO  - Immunity
VL  - 57
IS  - 11
SN  - 1074-7613
CY  - [Cambridge, Mass.]
PB  - Cell Press
M1  - DZNE-2025-00081
SP  - 2651 - 2668.e12
PY  - 2024
AB  - 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.
KW  - Animals
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Microglia: metabolism
KW  - Mice
KW  - Humans
KW  - Mice, Transgenic
KW  - Amyloid beta-Peptides: metabolism
KW  - Amyloidosis: metabolism
KW  - Amyloidosis: pathology
KW  - Amyloidosis: genetics
KW  - Apolipoproteins E: metabolism
KW  - Apolipoproteins E: genetics
KW  - Signal Transduction
KW  - Plaque, Amyloid: metabolism
KW  - Plaque, Amyloid: pathology
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - Disease Models, Animal
KW  - Lipid Metabolism
KW  - Protein Aggregation, Pathological
KW  - STAT Transcription Factors: metabolism
KW  - Janus Kinases: metabolism
KW  - Alzheimer’s disease (Other)
KW  - ApoE (Other)
KW  - inflammation (Other)
KW  - lipids (Other)
KW  - microglia (Other)
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Apolipoproteins E (NLM Chemicals)
KW  - STAT Transcription Factors (NLM Chemicals)
KW  - Janus Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:39419029
DO  - DOI:10.1016/j.immuni.2024.09.014
UR  - https://pub.dzne.de/record/275846
ER  -