Differential roles of the ubiquitin-proteasome system and autophagy in experimental models of Alzheimer's Disease

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and most prevalent form of dementia today. Current therapeutics are only capable of alleviating symptoms without targeting the root of the problem, as the pathogenesis of AD is still not completely clear. As pathological hallmarks of AD include the accumulation of β-amyloid (Aβ) and hyperphosphorylated tau protein aggregates, the current study examines whether impairments in protein degradation pathways, namely the ubiquitin-proteasome system and autophagy-lysosomal pathway, may play important roles in contributing to AD pathogenesis. Using primary cortical neuronal culture exposed to oligomeric Aβ as an in vitro model and triple transgenic (3xTg) AD mice as an in vivo model, this study examines longitudinal changes in protein degradation pathways and its relationship to tau accumulation and aggregation. How modulations of ubiquitin, a signaling protein involved in both proteasomal and autophagic degradation of target proteins, can mediate tau expression and aggregation was also explored. An initial impairment in proteasomal activity with a subsequent activation of the autophagy-lysosomal pathway was found both in vitro and in vivo. This corresponded with the changes in lysine residue 48 and 63- specific ubiquitin expression, which signals for proteasome and autophagic degradation of target proteins, respectively. Impairments in protein degradation resulted in an accumulation and aggregation of phosphorylated and non-phosphorylated forms of tau with the expression of ubiquitin mutants signaling for autophagic degradation attenuating this accumulation. In conclusion, this study shows the progression of the decline in proper protein degradation both in vitro and in vivo with modulation in ubiquitin signaling as a possible new therapeutic target for AD.