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

Acta Neuropathologica Communications

Lee-Way Jin¹  Thi Ngoc Anh Nguyen²  Yijuang Chern²  Ching-Pang Chang²  Pei-Yun Chuang²  Hui-Mei Chen²  Ya-Gin Chang²  Sin-Jhong Cheng³  Yung-Feng Liao⁴  Kuo-Chen Wu⁵  Fang-Yi Chou⁵  Chun-Jung Lin⁵  Vincent Huin⁶  Kevin Carvalho⁶  David Blum⁶  Luc Buée⁶ 

[1] Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA;Institute of Biomedical Sciences, Academia Sinica, 115, Nankang, Taipei, Taiwan;Institute of Biomedical Sciences, Academia Sinica, 115, Nankang, Taipei, Taiwan;Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan;Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan;School of Pharmacy, National Taiwan University, Taipei, Taiwan;Univ. Lille, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, 59000, Lille, France;Alzheimer & Tauopathies, LabEx DISTALZ, LiCEND, 59000, Lille, France;

关键词: Alzheimer’s disease;    Tauopathy;    Adenosine;    AMPK;    ENT1;   

DOI  :  10.1186/s40478-021-01213-7

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY