Cystatin C reduces the<i>in vitro</i>formation of soluble Aβ1‐42 oligomers and protofibrils

Abstract

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.

Keywords

Affiliated Institutions

• Lund University SE
• Lundbeck (Denmark) DK

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