Amyloid precursor protein (APP) proteolysis is essential for the production of β-amyloid peptides (Aβ) that form senile plaques in Alzheimer's disease (AD) brains. The β-site amyloid protein precursor cleaving enzyme 1 (BACE1) is the rate limiting enzyme in the generation of Aβ from APP, inhibition of BACE1 is thereby considered as an attractive strategy for anti-AD drug discovery. Chitosan oligosaccharides (COS) has been shown to possess various biological activities. Here we investigated the potential inhibitory effect of COS on both BACE1 expression in HEK293 APPswe cells and BACE1 enzymatic activity in vitro. The results showed that COS (100-500μg/ml) dose-dependently decreased the cell apoptosis, and potently repressed the secretion of both Aβ40 and Aβ42 as determined by ELISA. Moreover, treatment with COS resulted in a dramatic reduction in BACE1 mRNA and protein expression level, eIF2α phosphorylation as well as BACE1 enzymatic activity. Taken together, our findings indicate that COS can ameliorate Aβ-associated neurotoxicity, which may be, at least in part, attributable to reductions in BACE1 enzymatic activity and expression.
Keywords: Alzheimer's disease; Chitosan oligosaccharides; β-Amyloid peptide; β-Site amyloid precursor protein cleaving enzyme 1 (BACE1).
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