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Original

Cystatin C reduces the in vitro formation of soluble Aβ1‐42 oligomers and protofibrils

, , , &
Pages 179-190 | Received 13 Jun 2006, Accepted 07 Sep 2006, Published online: 08 Jul 2009
 

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 β‐amyloid protein (Aβ) 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 Aβ1‐42 significantly attenuated the in vitro formation of Aβ 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 Aβ oligomers. Direct binding of cystatin C to Aβ 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 Aβ to larger and perhaps more toxic molecular species in vivo.

Acknowledgements

This study was supported by the Medicon Valley Academy and the Swedish Science Research Council (Project no. 05196).

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