Activation of the γ-secretase complex and presence of γ-secretase-activating protein may contribute to Aβ42 production in sporadic inclusion-body myositis muscle fibers

The muscle-fiber phenotype of sporadic inclusion-body myositis (s-IBM), the most common muscle disease associated with aging, shares several pathological abnormalities with Alzheimer disease (AD) brain, including accumulation of amyloid-beta 42 (A beta 42) and its cytotoxic oligomers. The exact mechanisms leading to A beta 42 production within s-IBM muscle fibers are not known. A beta 42 and A beta 40 are generated after the amyloid-precursor protein (AOPP) is cleaved by beta-secretase and the gamma-secretase complex. A beta 42 is considered more cytotoxic than A beta 40, and it has a higher propensity to oligomerize, form amyloid fibrils, and aggregate. Recently, we have demonstrated in cultured human muscle fibers that experimental inhibition of lysosomal enzyme activities leads to A beta 42 oligomerization. In s-IBM muscle, we here demonstrate prominent abnormalities of the gamma-secretase complex, as evidenced by: a) increase of gamma-secretase components, namely active presenilin 1, presenilin enhancer 2, nicastrin, and presence of its mature, glycosylated form; b) increase of mRNAs of these gamma-secretase components; c) increase of gamma-secretase activity; d) presence of an active form of a newly-discovered gamma-secretase activating protein (GSAP); and e) increase of GSAP mRNA. Furthermore, we demonstrate that experimental inhibition of lysosomal autophagic enzymes in cultured human muscle fibers a) activates gamma-secretase, and b) leads to post-translational modifications of A beta PP and increase of A beta 42. Since autophagy is impaired in biopsied s-IBM muscle, the same mechanism might be responsible for its having increased gamma-secretase activity and A beta 42 production. Accordingly, improving lysosomal function might be a therapeutic strategy for s-IBM patients. (C) 2012 Elsevier Inc. All rights reserved.