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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

Molecular Neurobiology volume 55, pages 8936–8952 (2018)Cite this article

Abstract

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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Abbreviations

aCSF:

artificial cerebrospinal fluid

AD:

Alzheimer’s disease

ALS:

amyotrophic lateral sclerosis

AMC:

7-amino-4-methylcoumarin

APP:

amyloid precursor protein

AR:

adenosine receptor

BACE1:

β-site APP-cleaving enzyme 1

BBB:

blood-brain-barrier

BSA:

bovine serum albumin

CNS:

central nervous system

ECL:

enhanced chemiluminescence

ELISA:

enzyme-linked immunosorbent assay

ENTs:

equilibrative nucleoside transporters

ENT1:

equilibrative nucleoside transporter 1

fEPSPs:

field excitatory postsynaptic potentials

GFAP:

glial fibrillary acidic protein

GSK3β:

glycogen synthase kinase 3β

HD:

Huntington’s disease

HRP:

horseradish peroxidase

huAPP:

human amyloid precursor protein

IHC:

immunohistochemical

LTP:

long-term potentiation

LRP1:

lipoprotein receptor-related protein-1

MRI:

magnetic resonance imaging

MWM:

Morris water maze

NGS:

normal goat serum

PAGE:

polyacrylamide gel electrophoresis

PB:

phosphate buffer

PS1:

presenilin-1

RT:

room temperature

SAH:

S-adenosylhomocysteine

SCA3:

spinocerebellar ataxia type 3

SDS:

sodium dodecylsulfate

TBS:

theta burst stimulation

TBST:

Tris-buffered saline with 0.1% Tween-20

TMMC:

transgenic mouse models core

UPS:

ubiquitin proteasome system

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Acknowledgements

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

Funding

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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Author notes

  1. Chia-Chia Lee and Ching-Pang Chang contributed equally to this work.

Authors and Affiliations

  1. Institute of Biomedical Sciences, Academia Sinica, Nankang, Taipei, 115, Taiwan

    Chia-Chia Lee, Ching-Pang Chang, Hsing-Lin Lai, Sin-Jhong Cheng, Hui-Mei Chen, Yu-Ping Liao & Yijuang Chern

  2. School of Pharmacy, National Taiwan University, Taipei, Taiwan

    Chun-Jung Lin & Yu-Han Kao

  3. Neuroscience Program of Academia Sinica, Academia Sinica, Taipei, Taiwan

    Sin-Jhong Cheng

  4. Université de Lille, Inserm, CHU-Lille, LabEx DISTALZ, Jean-Pierre Aubert research centre UMR-S1172, Lille, France

    Emilie Faivre, Luc Buée & David Blum

  5. Department of Chemistry, National Taiwan University, Taipei, Taiwan

    Jim-Min Fang

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  1. Chia-Chia Lee
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Correspondence to Yijuang Chern.

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Conflict of Interest

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). https://doi.org/10.1007/s12035-018-1030-z

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  • DOI: https://doi.org/10.1007/s12035-018-1030-z

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