Elucidating the differential role of the ubiquitin-proteasome system and autophagy in experimental models of Alzheimer's disease

Abstract

Alzheimer’s disease (AD) is the most prevalent form of dementia, affecting over 44 million people worldwide today. There is no known cure with current therapeutics only capable of alleviating the symptoms rather than treating the root of the problem as the initiating factor in the development of AD is still unclear. A number of different theories have been proposed as to why β-amyloid (Aβ) and hyperphosphorylated tau protein, which subsequently form senile plaques and neurofibrillary tangles, respectively, accumulate within the brain of inflicted individuals. This study examines the notion that impairments in protein degradation pathways: the ubiquitin-proteasome system and autophagy-lysosomal pathway, is an important contributor to AD pathogenesis. Primary cortical neurons exposed to oligomeric Aβ is used as an in vitro model of AD while a triple transgenic (3xTg) AD model is used as an in vivo model. Using these two experimental models, 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 is also investigated. Lastly, whether pathological changes within the cortex of 3xTg AD brain can be found in the retina is also evaluated as a possible approach for the prompt diagnosis of AD. In vitro findings demonstrated an initial impairment in proteasomal activity with a subsequent activation of the autophagy-lysosomal pathway. This was confirmed with the formation of ubiquitin chains at lysine residue 48 and 63, which signals for proteasome and autophagic degradation of target proteins, respectively. Ubiquitin-tagged proteins were found to deposit within the cortex of 3xTg AD mice in a similar manner. Impairments in protein degradation resulted in increased expression and aggregation of both phosphorylated and non-phosphorylated forms of tau; while expression of ubiquitin mutants that promote formation of polyubiquitin chains signaling for protein degradation via the autophagy-lysosomal pathway was able to attenuate this accumulation. Substantial overlap in the presence of age-dependent changes in tau and ubiquitin was found in the retina and cortex of 3xTg AD mice as well. 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. Examination of protein deposition in the retina may be a useful tool in reflecting the condition of proteinopathy within the brain in real time for better diagnosis and treatment of patients with AD.