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

被引：14

作者：

Chang, Ching-Pang ^{[1
]}

Chang, Ya-Gin ^{[1
]}

Chuang, Pei-Yun ^{[1
]}

Nguyen, Thi Ngoc Anh ^{[1
]}

Wu, Kuo-Chen ^{[2
]}

Chou, Fang-Yi ^{[2
]}

Cheng, Sin-Jhong ^{[1
,3
]}

Chen, Hui-Mei ^{[1
]}

Jin, Lee-Way ^{[4
]}

Carvalho, Kevin ^{[6
]}

Huin, Vincent ^{[5
,6
]}

Buee, Luc ^{[5
,6
]}

Liao, Yung-Feng ^{[5
,7
]}

Lin, Chun-Jung ^{[2
]}

Blum, David ^{[5
,6
]}

Chern, Yijuang ^{[1
]}

机构：

[1] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan

[2] Natl Taiwan Univ, Sch Pharm, Taipei, Taiwan

[3] Acad Sinica, Neurosci Program, Taipei, Taiwan

[4] Univ Calif Davis, Dept Pathol & Lab Med, Sacramento, CA 95817 USA

[5] Univ Lille, CHU Lille, INSERM, LilNCog Lille Neurosci & Cognit U1172, F-59000 Lille, France

[6] LiCEND, LabEx DISTALZ, Alzheimer & Tauopathies, F-59000 Lille, France

[7] Acad Sinica, Inst Cellular & Organism Biol, Taipei, Taiwan

来源：

ACTA NEUROPATHOLOGICA COMMUNICATIONS | 2021年 / 9卷 / 01期

基金：

美国国家卫生研究院;

关键词：

Alzheimer's disease; Tauopathy; Adenosine; AMPK; ENT1; ACTIVATED PROTEIN-KINASE; TAU TRANSGENIC MICE; ALZHEIMERS-DISEASE; MOUSE MODEL; ADENOSINE RECEPTORS; PHOSPHORYLATION; EXPRESSION; NEURONS; MEMORY; DEFICITS;

D O I：

10.1186/s40478-021-01213-7

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

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.

引用

页数：18

共 73 条

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