Cystatin C Protects Neuronal Cells from Amyloid-beta-induced Toxicity

Multiple studies suggest that cystatin C (CysC) has a role in Alzheimer's disease (AD) and a decrease in CysC secretion is linked to the disease in patients with a polymorphism in the CysC gene. CysC binds amyloid-beta (A beta) and inhibits formation of A beta fibrils and oligomers both in vitro and in mouse models of amyloid deposition. Here we studied the effect of CysC on cultured primary hippocampal neurons and a neuronal cell line exposed to either oligomeric or fibrillar cytotoxic forms of A beta. The extracellular addition of the secreted human CysC together with preformed either oligomeric or fibrillar A beta increased cell survival. While CysC inhibits A beta aggregation, it does not dissolve preformed A beta fibrils or oligomers. Thus, CysC has multiple protective effects in AD, by preventing the formation of the toxic forms of A beta and by direct protection of neuronal cells from A beta toxicity. Therapeutic manipulation of CysC levels, resulting in slightly higher concentrations than physiological could protect neuronal cells from cell death in AD.