Inflammation induces tau pathology in inclusion body myositis model via glycogen synthase kinase-3β

Objective: Inclusion body myositis (IBM) is an inflammatory muscle disease, although the role of inflammation remains to be elucidated. Here, we address the mechanisms by which inflammation modulates A beta and tau, two hallmark features of this disease. Methods: A transgenic mouse model of IBM was utilized in which acute and chronic inflammation was induced via lipopolysaccharide. The effects of inflammation were assessed by analyzing the myopathological and the behavioral phenotype. Human IBM skeletal muscle biopsies were investigated to determine concordance with data from the animal model. Results: Both acute and chronic lipopolysaccharide exposure augmented infiltration by CD(8+) cytotoxic T cells and increased amyloid precursor protein steady-state levels in skeletal muscle, whereas increased A beta generation was observed only in chronically treated mice. Both acute and chronic inflammation enhanced tau phosphorylation in skeletal muscle. The mechanism underlying this effect was mediated by the tau kinase, glycogen synthase kinase-3 beta (GSK-3 beta). Suppression of GSK-3 beta activity using either a specific inhibitor or lithium chloride significantly reduced tau phosphorylation and partially rescued motor impairment. In human IBM muscle, GSK-3 beta and phospho-tau were colocalized, further Supporting the pathogenic role of GSK-3 beta in this disease. Using C(2)C12 myoblast cultures, we found that GSK-3 beta was activated by proinflammatory cytokines (interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha), leading to enhanced tau phosphorylation. Interpretation: Our results identify a molecular mechanism by which proinflammatory stimuli affect tau pathology via the GSK-3 beta signaling pathway in skeletal muscle.