Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy - Inserm - Institut national de la santé et de la recherche médicale Access content directly
Journal Articles Acta Neuropathologica Communications Year : 2021

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

Abstract

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.

Domains

Neurobiology
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Dates and versions

inserm-03366697 , version 1 (05-10-2021)

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Ching-Pang Chang, Ya-Gin Chang, Pei-Yun Chuang, Thi Ngoc Anh Nguyen, Kuo-Chen Wu, et al.. Equilibrative nucleoside transporter 1 inhibition rescues energy dysfunction and pathology in a model of tauopathy. Acta Neuropathologica Communications, 2021, 9 (1), pp.112. ⟨10.1186/s40478-021-01213-7⟩. ⟨inserm-03366697⟩
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