Cystatin C reduces the in vitro formation of soluble A beta 1-42 oligomers and protofibrils

There are an increasing number of genetic and neuropathological observations to suggest that cystatin C, an extracellular protein produced by all nucleated cells, might play a role in the pathophysiology of sporadic Alzheimer's disease (AD). Recent observations indicate that small and large soluble oligomers of the beta-amyloid protein (A beta) impair synaptic plasticity and induce neurotoxicity in AD. The objective of the present study was to investigate the influence of cystatin C on the production of such oligomers in vitro. Co-incubation of cystatin C with monomeric A beta 1-42 significantly attenuated the in vitro formation of A beta oligomers and protofibrils, as determined using electron microscopy (EM), dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, thioflavin T (ThT) spectrofluorimetry and gel chromatography. However, cystatin C did not dissolve preformed A beta oligomers. Direct binding of cystatin C to A beta was demonstrated with the formation of an initial 1:1 molar high-affinity complex. These observations suggest that cystatin C might be a regulating element in the transformation of monomeric A beta to larger and perhaps more toxic molecular species in vivo.