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Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease


Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and synaptic dysfunction. Adenosine is an important homeostatic modulator that controls the bioenergetic network in the brain through regulating receptor-evoked signaling pathways, bioenergetic machineries, and epigenetic-mediated gene regulation. Equilibrative nucleoside transporter 1 (ENT1) is a major adenosine transporter that recycles adenosine from the extracellular space. In the present study, we report that a small adenosine analogue (designated J4) that inhibited ENT1 prevented the decline in spatial memory in an AD mouse model (APP/PS1). Electrophysiological and biochemical analyses further demonstrated that chronic treatment with J4 normalized the impaired basal synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses as well as the aberrant expression of synaptic proteins (e.g., NR2A and NR2B), abnormal neuronal plasticity-related signaling pathways (e.g., PKA and GSK3β), and detrimental elevation in astrocytic A2AR expression in the hippocampus and cortex of APP/PS1 mice. In conclusion, our findings suggest that modulation of adenosine homeostasis by J4 is beneficial in a mouse model of AD. Our study provides a potential therapeutic strategy to delay the progression of AD.

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artificial cerebrospinal fluid


Alzheimer’s disease


amyotrophic lateral sclerosis




amyloid precursor protein


adenosine receptor


β-site APP-cleaving enzyme 1




bovine serum albumin


central nervous system


enhanced chemiluminescence


enzyme-linked immunosorbent assay


equilibrative nucleoside transporters


equilibrative nucleoside transporter 1


field excitatory postsynaptic potentials


glial fibrillary acidic protein


glycogen synthase kinase 3β


Huntington’s disease


horseradish peroxidase


human amyloid precursor protein




long-term potentiation


lipoprotein receptor-related protein-1


magnetic resonance imaging


Morris water maze


normal goat serum


polyacrylamide gel electrophoresis


phosphate buffer




room temperature




spinocerebellar ataxia type 3


sodium dodecylsulfate


theta burst stimulation


Tris-buffered saline with 0.1% Tween-20


transgenic mouse models core


ubiquitin proteasome system


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We are grateful to Dr. Yun-Lian Lin for helpful suggestions.


This research was supported by the Academia Sinica and Ministry of Science and Technology (MOST 104-0210-01-09-02, MOST 105-0210-01-13-01, MOST 106-0210-01-15-02). The Alzheimer & Tauopathies laboratory is supported by Inserm, Université Lille, France Alzheimer, programs d’investissements d’avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), ANR (ADORATAU and SPREADTAU), Fondation pour la Recherche Médicale, Vaincre Alzheimer, Fondation Plan Alzheimer, Lille Métropole Communauté Urbaine, Région Hauts-de-France (COGNADORA), and DN2M. A collaboration between Academia Sinica and Inserm has been promoted thanks to PHC Orchid exchange funding.

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Correspondence to Yijuang Chern.

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Yijuang Chern and Jim-Min Fang hold patents in adenosine compounds for the treatment of neurodegenerative diseases.

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Lee, CC., Chang, CP., Lin, CJ. et al. Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer’s Disease. Mol Neurobiol 55, 8936–8952 (2018).

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