Cystatin C promotes tau protein phosphorylation and causes microtubule instability by inhibiting intracellular turnover of GSK3β in neurons

In Alzheimer's disease (AD) tau protein hyperphosphorylation causes neurofibrillary tangle formation, microtubule instability and neurodegeneration. Determining the mechanism of tau hyperphosphorylation will provide a better understanding of AD pathology. Cystatin C (CysC) is a risk factor for late-onset AD and its level is upregulated in the brains of AD patients. The role of CysC is AD pathogenesis is not known. In this study, we found that CysC level is upregulated in 3xTg-AD mouse brain. We demonstrate that CysC does not affect cellular Aβ production. However, when overexpressed in neuron (NGF-differentiated PC12 cells), CysC inhibits turnover of GSK3β, promotes GSK3β-catalyzed tau phosphorylation at Ser396/404 and causes microtubule instability. Our data provide a novel insight into the role of CysC in AD pathogenesis. •Cystatin C is one of the risk factors for LOAD.•Cystatin C does not affect Aβ production in HEK-293 cells.•Cystatin C promotes GSK3β-catalyzed tau protein phosphorylation in neurons.•Cystatin C inhibits cellular degradation of GSK3β.