EPAC2 knockout causes abnormal tau pathology through calpain-mediated CDK5 activation
De-Yi Liu, He‐Zhou Huang, Li Ke, Youming Lu, Ling‐Qiang Zhu
Abstract
Tau pathology, including aberrant tau hyperphosphorylation, aggregation, and mislocalization, is implicated in many neurodegenerative disorders, including Alzheimer’s disease (AD), which is the most prevalent dementia among the elderly. A better understanding of the molecular mechanisms underlying tau pathology should help advance therapies for neurodegenerative diseases. Perturbations in cyclic adenosine monophosphate (cAMP)-dependent signaling play an important role in the pathophysiology of numerous neurological diseases. EPAC2 is an intracellular cAMP receptor whose expression is downregulated in AD. However, the involvement and role of EPAC2 in tau pathology remain unclear. In this study, we report for the 1st time that EPAC2 is downregulated in the hippocampus of Tg2576 mice, a widely used transgenic mouse model of familial AD. Furthermore, genetic deletion of EPAC2 resulted in abnormal hyperphosphorylation at multiple sites on tau. Aberrant tau aggregation and abnormal neuronal morphology were also detected in these EPAC2−/− mice. Administration of inhibitors of CDK5 or calpain effectively rescued the tau pathology in EPAC2−/− mice. This suggests that the activation of CDK5 by calpain plays an important role in the development of tau pathology in these EPAC2−/− mice. Collectively, our findings demonstrate a direct link between EPAC2 and tau pathology, and suggest that the EPAC2 and calpain/CDK5 signaling pathways may have potential as therapeutic targets for AD.