ORCID: https://orcid.org/0000-0003-4422-7410; Wefers, Benedikt ORCID: https://orcid.org/0000-0002-2492-9389; Schifferer, Martina ORCID: https://orcid.org/0000-0002-0500-8218; Willem, Michael; Nave, Klaus-Armin; Haass, Christian ORCID: https://orcid.org/0000-0002-4869-1627; Arzberger, Thomas; Jäkel, Sarah; Wirths, Oliver ORCID: https://orcid.org/0000-0002-4115-0334; Saher, Gesine ORCID: https://orcid.org/0000-0003-3507-9604 und Simons, Mikael ORCID: https://orcid.org/0000-0001-5329-192X
(2024):
Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis.
In: Immunity, Vol. 57, No. 11: pp. 2651-2668
[PDF, 11MB]
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.
| Item Type: | Journal article |
|---|---|
| Faculties: | Medicine > Adolf Butenandt Institute Medicine > Munich Cluster for Systems Neurology (SyNergy) Medicine > Institute for Stroke and Dementia Research (ISD) Medicine > Medical Center of the University of Munich > Neurological Clinic and Polyclinic with Friedrich Baur Institute Medicine > Medical Center of the University of Munich > Clinic and Polyclinic for Psychiatry and Psychotherapy |
| Subjects: | 600 Technology > 610 Medicine and health |
| URN: | urn:nbn:de:bvb:19-epub-123269-6 |
| ISSN: | 1074-7613 |
| Annotation: | Correction published online December 4, 2024 |
| Language: | English |
| Item ID: | 123269 |
| Date Deposited: | 23. Dec 2024 06:55 |
| Last Modified: | 23. Dec 2024 06:55 |
| DFG: | Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198 |
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