In A beta PP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of A beta PP751 and GSK3 beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis

Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-beta (A beta)-precursor protein 751 (A beta PP751), A beta, phosphorylated tau, and other 'Alzheimer-characteristic' proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer's disease (AD) patients and AD transgenic-mouse models, phosphorylation of neuronal A beta PP695 (p-A beta PP) on Thr668 (equivalent to T724 of A beta PP751) is considered detrimental because it increases generation of cytotoxic A beta and induces tau phosphorylation. Activated glycogen synthase kinase3 beta (GSK3 beta) is involved in phosphorylation of both A beta PP and tau. Lithium, an inhibitor of GSK3 beta, was reported to reduce levels of both the total A beta PP and p-A beta PP in AD animal models. In relation to s-IBM, we now show for the first time that (1) In A beta PP-overexpressing cultured human muscle fibers (human muscle culture IBM model: (a) proteasome inhibition significantly increases GSK3 beta activity and A beta PP phosphorylation, (b) treatment with lithium decreases (i) phosphorylated-A beta PP, (ii) total amount of A beta PP, (iii) A beta oligomers, and (iv) GSK3 beta activity; and (c) lithium improves proteasome function. (2) In biopsied s-IBM muscle fibers, GSK3 beta is significantly activated and A beta PP is phosphorylated on Thr724. Accordingly, treatment with lithium, or other GSK3 beta inhibitors, might benefit s-IBM patients.