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

Abstract

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 Aβ 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 CD8⁺ cytotoxic T cells and increased amyloid precursor protein steady-state levels in skeletal muscle, whereas increased Aβ 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-3β (GSK-3β). Suppression of GSK-3β activity using either a specific inhibitor or lithium chloride significantly reduced tau phosphorylation and partially rescued motor impairment. In human IBM muscle, GSK-3β and phospho-tau were colocalized, further supporting the pathogenic role of GSK-3β in this disease. Using C2C12 myoblast cultures, we found that GSK-3β was activated by proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor-α), leading to enhanced tau phosphorylation.

Interpretation

Our results identify a molecular mechanism by which proinflammatory stimuli affect tau pathology via the GSK-3β signaling pathway in skeletal muscle. Ann Neurol 2008