A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function

Yamei Wang; Jianhao Wang; Hongyu Chen; Xiang Li; Ruifeng Xu; Feng Gao; Hang Yu; Fang Li; Dongdong Qin; Jiabei Wang; Yuke Shi; Yiyi Li; Songyan Liu; Xi Zhang; Shuai Ding; Yiqian Hu; Liqin Huang; Xin-Ya Gao; Zuneng Lu; Jin Luo; Zhi-Hao Wang

doi:10.3389/fnagi.2023.1293164

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function

Front Aging Neurosci. 2023 Dec 6:15:1293164. doi: 10.3389/fnagi.2023.1293164. eCollection 2023.

Authors

Yamei Wang^#^{1

2}, Jianhao Wang^#^{1

2}, Hongyu Chen^#^{1

2}, Xiang Li^{1

2}, Ruifeng Xu³, Feng Gao^{1

2}, Hang Yu^{1

2}, Fang Li^{1

2}, Dongdong Qin^{1

2}, Jiabei Wang^{1

2}, Yuke Shi^{1

2}, Yiyi Li^{1

2}, Songyan Liu^{1

2}, Xi Zhang^{1

2}, Shuai Ding^{1

2}, Yiqian Hu^{1

2}, Liqin Huang^{1

2}, Xin-Ya Gao^{4

5}, Zuneng Lu^{1

2}, Jin Luo⁶, Zhi-Hao Wang^{1

2}

Affiliations

¹ Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
² Center for Neurodegenerative Disease Research, Renmin Hospital of Wuhan University, Wuhan, China.
³ Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁴ Department of Neurology, Henan Provincial People's Hospital, Zhengzhou, China.
⁵ Laboratory of Neurology, Henan Provincial People's Hospital, Zhengzhou, China.
⁶ Center for Reproductive Medicine, Renmin Hospital of Wuhan University, Wuhan, China.

^# Contributed equally.

Abstract

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-β peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear.

Methods: Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS.

Results: We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice.

Conclusion: These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.

Keywords: Alzheimer’s disease; PPAR-δ; depression; mitochondria; tau.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (No. 82101479) to Z-HW, National Key Research Projects of China (No. 2021YFA1302400) to Z-HW.