Cystatin C colocalizes with amyloid‐β and coimmunoprecipitates with amyloid‐β precursor protein in sporadic inclusion‐body myositis muscles

Abstract Cystatin C (CC), an endogenous cysteine protease inhibitor, is accumulated within amyloid‐β (Aβ) amyloid deposits in Alzheimer's disease (AD) brain and was proposed to play a role in the AD pathogenesis. Because the chemo‐morphologic muscle phenotype of sporadic inclusion‐body myositis (s‐IBM) has several similarities with the phenotype of AD brain, including abnormal accumulation of Aβ deposits, we studied expression and localization of CC in muscle biopsies of 10 s‐IBM, and 16 disease‐ and five normal‐control muscle biopsies. Physical interaction of CC with amyloid‐β precursor protein (AβPP) was studied by a combined immunoprecipitation/immunoblotting technique in the s‐IBM muscle biopsies and in AβPP‐overexpressing cultured human muscle fibers. In all s‐IBM muscle biopsies, CC‐immunoreactivity either colocalized with, or was adjacent to, the Aβ‐immunoreactive inclusions in 80–90% of the vacuolated muscle fibers, mostly in non‐vacuolated regions of their cytoplasm. Ultrastructurally, CC immunoreactivity‐colocalized with Aβ on 6–10 nm amyloid‐like fibrils and floccular material. By immunoblotting, CC expression was strongly increased in IBM muscle as compared to the controls. By immunoprecipitation/immunoblotting experiments, CC coimmunoprecipitated with AβPP, both in s‐IBM muscle and in AβPP‐overexpressing cultured normal human muscle fibers. Our studies (i) demonstrate for the first time that CC physically associates with AβPP, and (ii) suggest that CC may play a novel role in the s‐IBM pathogenesis, possibly by influencing AβPP processing and Aβ deposition.