Phosphorylation-state dependent modulation of Aβ pathobiology in Alzheimer's disease : Intraneuronal phosphorylated Aβ induced subcellular dysfunction and microglial inflammation

Progressive accumulation of Aβ aggregates as extracellular plaques is a characteristic hallmark of AD. Alternative processing of APP and/or further peptidic cleavages, results in the generation of Aβ peptides with various lengths. In addition, multiple post-translationally modified Aβ variants have also been reported. Extracellular Aβ can be phosphorylated by secreted and cell-surface localized protein kinases, and phosphorylated Aβ (pAβ) peptides showed differential aggregation characteristics and exert higher cytotoxicity compared to the non-phosphorylated variant (npAβ). pAβ species also exhibit differential deposition in transgenic mouse models and human AD brains. The research in this PhD project was focused on elucidating the molecular and cellular mechanisms that contribute to pAβ-associated neurotoxicity. Primarily, the effect of phosphorylation on Aβ oligomerization properties was analyzed. The data indicate that Aβ phosphorylated at serine residue 8 (pSer8Aβ) formed higher molecular weight soluble oligomeric species. On the other hand, phosphorylation at serine residue 26 (pSer26Aβ), resulted in the formation of low and intermediate weight soluble oligomers. This behavior was completely different when compared to the insoluble fibrillar species formed by npAβ peptides. Importantly, pAβ variants exerted increased neurotoxicity as compared to the npAβ peptides. Secondly, the impact of phosphorylation-state specific Aβ variants on neuronal autophagy and the endo-lysosomal pathway (ALP) as well as ubiquitin proteasomal systems (UPS), were investigated. The relation of pAβ species with respect to neuronal proteostasis (ALP and UPS) in an APP-PSEN1 transgenic AD mouse models, and as well as in vitro cell culture and primary neuronal models was examined. The results demonstrate that phosphorylation-state dependent intraneuronal accumulation and vesicular sorting of Aβ resulted in differential effects on the functioning of ALP, UPS, endoplasmic reticulum (ER) stress response, and mitochondria, suggesting a ...