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Advanced Neurology

ORIGINAL RESEARCH ARTICLE
EPAC2 knockout causes abnormal tau pathology

through calpain-mediated CDK5 activation

De-Yi Liu , He-Zhou Huang , Ke Li , Youming Lu , and Ling-Qiang Zhu *
1,2
1
1
1
1
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

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
1 time that EPAC2 is downregulated in the hippocampus of Tg2576 mice, a widely
st
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
−/−
*Corresponding author: EPAC2 mice. Administration of inhibitors of CDK5 or calpain effectively rescued the
−/−
Ling-Qiang Zhu (zhulq@mail.hust. tau pathology in EPAC2 mice. This suggests that the activation of CDK5 by calpain
edu.cn) plays an important role in the development of tau pathology in these EPAC2
−/−
Citation: Liu D-Y, Huang H-Z, Li K, mice. Collectively, our findings demonstrate a direct link between EPAC2 and tau
et al., 2022, EPAC2 knockout pathology, and suggest that the EPAC2 and calpain/CDK5 signaling pathways may
causes abnormal tau pathology have potential as therapeutic targets for AD.
through calpain-mediated CDK5
activation, Adv Neuro, 1(1): 8.
https://doi.org/10.36922/an.v1i1.8
Keywords: CDK5; Tau pathology; EPAC2
Received: November 30, 2021
Accepted: February 22, 2022
Published Online: March 16, 2022 1. Introduction
Copyright: © 2022 Author(s).
This is an Open-Access article Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders
distributed under the terms of the in the elderly. AD is clinically characterized by progressive cognitive decline
Creative Commons Attribution accompanied by other psychiatric disorders. An autopsy study showed that intracellular
License, permitting distribution,
and reproduction in any medium, neurofibrillary tangles (NFTs) and extracellular senile plaques (SPs) in neurons are the
[1]
provided the original work is two major pathological hallmarks of AD brains . NFTs are composed of abnormally
properly cited. hyperphosphorylated microtubule-associated protein tau. Normal tau promotes
Publisher’s Note: AccScience the aggregation of tubulins and maintains the stability of microtubules. In contrast,
Publishing remains neutral with hyperphosphorylated tau loses these normal functions and acquires the ability to form
regard to jurisdictional claims in
published maps and institutional paired helical filaments that induce synaptic degeneration and neuronal loss. Studies
affiliations. suggest that NFTs are more closely related to cognitive decline in the progression of

Volume 1 Issue 1 (2022) 1 https://doi.org/10.36922/an.v1i1.8