Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy

Acta Neuropathologica Communications - Tập 9 - Trang 1-18 - 2021
Ching-Pang Chang1, Ya-Gin Chang1, Pei-Yun Chuang1, Thi Ngoc Anh Nguyen1, Kuo-Chen Wu2, Fang-Yi Chou2, Sin-Jhong Cheng1,3, Hui-Mei Chen1, Lee-Way Jin4, Kevin Carvalho5,6, Vincent Huin5,6, Luc Buée5,6, Yung-Feng Liao7, Chun-Jung Lin2, David Blum5,6, Yijuang Chern1
1Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, Taiwan
2School of Pharmacy, National Taiwan University, Taipei, Taiwan
3Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan
4Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, USA
5Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, Lille, France
6Alzheimer & Tauopathies, LabEx DISTALZ, LiCEND, Lille, France
7Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan

Tóm tắt

Tau pathology is instrumental in the gradual loss of neuronal functions and cognitive decline in tauopathies, including Alzheimer’s disease (AD). Earlier reports showed that adenosine metabolism is abnormal in the brain of AD patients while consequences remained ill-defined. Herein, we aimed at investigating whether manipulation of adenosine tone would impact Tau pathology, associated molecular alterations and subsequent neurodegeneration. We demonstrated that treatment with an inhibitor (J4) of equilibrative nucleoside transporter 1 (ENT1) exerted beneficial effects in a mouse model of Tauopathy. Treatment with J4 not only reduced Tau hyperphosphorylation but also rescued memory deficits, mitochondrial dysfunction, synaptic loss, and abnormal expression of immune-related gene signatures. These beneficial effects were particularly ascribed to the ability of J4 to suppress the overactivation of AMPK (an energy reduction sensor), suggesting that normalization of energy dysfunction mitigates neuronal dysfunctions in Tauopathy. Collectively, these data highlight that targeting adenosine metabolism is a novel strategy for tauopathies.

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