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.
Congratulations to Prof. Mikael Simons from Technical University Munich (Germany) and co-authors for their wonderful work published in Immunity (IF=34)!
InvivoChem is proud to provide Professor Mikael Simons with our high-quality product Baricitinib (Cat #: V0338; CAS #: 1187594-09-7, JAK1 and JAK2 inhibitor) for this research.
References: Immunity. 2024 Nov 12;57(11):2651-2668.e12. doi: 10.1016/j.immuni.2024.09.014.
