EPAC2 knockout causes abnormal tau pathology through calpain-mediated CDK5 activation

¹ Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China

² Department of Pathophysiology, School of Basic Medicine, Chongqing Medical University, Chongqing, 400016, China

Advanced Neurology 2022, 1(1), 8 https://doi.org/10.36922/an.v1i1.8

Submitted: 30 November 2021 | Accepted: 22 February 2022 | Published: 16 March 2022

© 2022 by the Authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

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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.

Keywords

CDK5

Tau pathology

EPAC2

Funding

National Natural Science Foundation of China

National Key Research and Development Program of China

Top-Notch Young Talents Program of China

Conflict of interest

The authors have no conflicts of interest to declare.

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