Chaperone-mediated Autophagy For Degrading Alzheimer-associated Toxic Peptides

Background: Chaperone-mediated autophagy(CMA) is implicated in selective turnover of soluble proteins that are prone to aggregation in neurodegenerative diseases. Although recent results suggest that overexpression of molecular chaperones could provide cytoprotection against amyloid-β(Aβ), there is a lack of evidence directly supporting the pivotal role of CMA pathway in the pathogenesis of Alzheimer’s disease(AD).Purpose: To investigate the hypothesis that CMA is involved in clearance of the neurotoxic peptides derived from amyloid precursor protein(APP) cleavage in AD process.Methods: The involvement of CMA in clearance of the neurotoxic peptides derived from APP cleavage was confirmed by overexpression or silencing of CMA-related proteins in-vitro and in-vivo. Levels of neurotoxic peptides were measured by ELISA kit or immunoblot analysis. In addition, we employed recombinant adenovirus-mediated gene brain delivery to overexpression of CMA-related proteins in APPswe/PS1 d E9 brain. The spatial learning and memory performance was detected by Morris water maze. The distribution of Aβ was assessed by immunohistochemical analysis in brain section. And the neuronal morphology was observed by Nissl staining.Results: Using APPswe/PS1 d E9 transgenic mice model of AD, we firstly found there was reduced CMA activity in the brain. Our study further investigated the regulatory role of CMA components in degradation of Aβ in-vitro and in-vivo. The reduction in CMA related proteins affected the accumulation of neurotoxic peptides while increase in CMA related proteins affected the accumulation of neurotoxic peptides.Furthermore, overexpression of CMA-related protein alleviated neuropathology and rescued early cognitive deficits in APPswe/PS1 d E9 mice. Moreover, induction of CMA through in-vivo injection of recombinant adenovirus vectors effectively decreased soluble Aβ levels, and ameliorated Aβ-induced neurodegeneration and cognitive deficits in APPswe/PS1 d E9 mice.Conclusions: Our findings identify that CMA is an essential pathway for degrading neurotoxic peptides in AD process, and modulation of CMA represents a novel therapeutic intervention for AD.