Age-related shift in LTD is dependent on neuronal adenosine A2A receptors interplay with mGluR5 and NMDA receptors

Mariana Temido‐Ferreira ,Christa E Müller,Inês Marques-Morgado,Hélène Marie,Vânia L Batalha,José Pimentel,Luc Buée,Diana G Ferreira,Serge N Schiffmann,Michael Bäder ,Valérie Buée‐Scherrer ,Paula M Canas,Andreia Pinto,Sara Carvalho,Rodrigo A Cunha,Émilie Faivre ,Rui Gomes,Joana Coelho ,Younis Baqi,Paula A Pousinha,Tiago F Outeiro,Laetitia Cuvelier,Pedro Pereira,David Blum,Luı́sa V Lopes

doi:10.1038/s41380-018-0110-9

Abstract

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A2A receptor (A2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A2AR in age-related conditions. We report, for the first time, a significant overexpression of A2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca2+ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A2AR blockade. This A2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.

Highlights

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline [1]
In humans, several epidemiological studies have shown that regular caffeine consumption attenuates memory disruption during aging and decreases the risk of developing memory impairments in AD patients [34, 40,41,42,43]
There was a significant increase in A2A receptor (A2AR) protein levels in the aged forebrain that was further enhanced in samples from AD patients (Fig. 1a, b)

Summary

Introduction

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline [1]. In age-related neurodegeneration, cognitive decline has a stronger correlation to early synapse loss than neuronal loss in patients [2]. Despite the many clinical trials conducted to identify drug targets that could reduce protein toxicity in AD, such targets and such strategies proven unsuccessful. Efforts focused on identifying the early mechanisms of disease pathogenesis, driven or exacerbated by the aging process, may prove more relevant to slow the progression rather than the current disease-based models. Extended author information available on the last page of the article

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Conclusion