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

Ching Pang Chang, Ya Gin Chang, Pei Yun Chuang, Thi Ngoc Anh Nguyen, Kuo Chen Wu, Fang Yi Chou, Sin Jhong Cheng, Hui Mei Chen, Lee Way Jin, Kevin Carvalho, Vincent Huin, Luc Buée, Yung Feng Liao, Chun Jung Lin, David Blum, Yijuang Chern

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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. [Figure not available: see fulltext.]

Original languageEnglish (US)
Article number112
JournalActa Neuropathologica Communications
Issue number1
StatePublished - Dec 2021


  • Adenosine
  • Alzheimer’s disease
  • AMPK
  • ENT1
  • Tauopathy

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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