THE ROLE OF HSP60 IN AMYLOID BETA PATHWAY: RELEVANCE TO ALZHEIMER’S DISEASE

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder affecting more than 40 million individuals worldwide. The high number of factors triggering the onset of AD justifies the current absence of disease-modifying therapies. The involved pathological mechanisms are still elusive and, therefore, the finding of effective therapies requires further elucidation of biomolecular mechanisms controlling AD pathogenesis. Particularly, the aberrant amyloidogenic cleavage of amyloid precursor protein (APP), amyloid beta (Aβ) peptide misfolding and oligomerization, and the impairment of the protein quality control machinery are key hallmarks characterizing the onset of the disease. Furthermore, evidence suggests that the age-related impairments of chaperones, a class of modulatory proteins involved in the protein quality control of the cell, contributes to the neurotoxicity induced by Aβ oligomers, but the underlying mechanism remains unresolved. In the present work, we characterized the functional interaction between Aβ and the mitochondrial chaperon Hsp60 using cell free, in vitro and ex vivo approaches to test if Hsp60 can protect against Aβ toxicity. Specifically, cell free experiment using chromatography, atomic force microscopy and spectroscopy suggested the inhibitory effect of Hsp60 on amyloid aggregation. In vitro investigations using Chinese Hamster Ovary (CHO) cell line overexpressing human APP751 variant of APP (7PA2 cell line), a model of human Aβ oligomer production, were used, along with immunocytochemistry, ELISA and western blotting techniques, to investigate the effect of Hsp60 overexpression on Aβ production and localization in different sub-cellular compartments. The effect of Hsp60 on Aβ-induced cytotoxicity has been also investigated in vitro using neuroblastoma cell line. Our data suggest that Hsp60 directly interferes with either with APP processing and the release of Aβ in the extracellular environment, leading to reduced Aβ production and Aβ aggregation into toxic oligomers thus proposing Hsp60 as an attractive target for future AD therapies.