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

  • Chia-Chia Lee
  • Ching-Pang Chang
  • Chun-Jung Lin
  • Hsing-Lin Lai
  • Yu-Han Kao
  • Sin-Jhong Cheng
  • Hui-Mei Chen
  • Yu-Ping Liao
  • Emilie Faivre
  • Luc Buée
  • David Blum
  • Jim-Min Fang
  • Yijuang Chern
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.

Keywords

Alzheimer’s disease Adenosine ENT1 PKA Glutamate receptors 

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

Notes

Acknowledgements

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

Compliance with Ethical Standards

Conflict of Interest

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

Supplementary material

12035_2018_1030_MOESM1_ESM.docx (23.2 mb)
ESM 1 (DOCX 23.1 MB)

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Chia-Chia Lee
    • 1
  • Ching-Pang Chang
    • 1
  • Chun-Jung Lin
    • 2
  • Hsing-Lin Lai
    • 1
  • Yu-Han Kao
    • 2
  • Sin-Jhong Cheng
    • 1
    • 3
  • Hui-Mei Chen
    • 1
  • Yu-Ping Liao
    • 1
  • Emilie Faivre
    • 4
  • Luc Buée
    • 4
  • David Blum
    • 4
  • Jim-Min Fang
    • 5
  • Yijuang Chern
    • 1
  1. 1.Institute of Biomedical SciencesAcademia SinicaTaipeiTaiwan
  2. 2.School of PharmacyNational Taiwan UniversityTaipeiTaiwan
  3. 3.Neuroscience Program of Academia SinicaAcademia SinicaTaipeiTaiwan
  4. 4.Université de Lille, Inserm, CHU-Lille, LabEx DISTALZJean-Pierre Aubert research centre UMR-S1172LilleFrance
  5. 5.Department of ChemistryNational Taiwan UniversityTaipeiTaiwan

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