Beneficial Effect of a Selective Adenosine A2A Receptor Antagonist in the APPswe/PS1dE9 Mouse Model of Alzheimer's Disease.

Émilie Faivre ,Christa E Müller,Younis Baqi,Sabiha Eddarkaoui,Nicolas Sergeant,Martin Figeac,Katja Zornbach,Luc Buée,Shéhérazade Sebda,Raphaëlle Caillierez,Annett Halle,Yijuang Chern,Lucrezia Cellai,Marion Schneider,David Blum,Kévin Carvalho ,Joana Coelho ,Luı́sa V Lopes ,Michael T Heneka ,Enas M Malik

doi:10.3389/fnmol.2018.00235

Abstract

Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer’s disease (AD) and mitigates both amyloid and Tau lesions in transgenic mouse models of the disease. While short-term treatment with A2AR antagonists have been shown to alleviate cognitive deficits in mouse models of amyloidogenesis, impact of a chronic and long-term treatment on the development of amyloid burden, associated neuroinflammation and memory deficits has never been assessed. In the present study, we have evaluated the effect of a 6-month treatment of APPsw/PS1dE9 mice with the potent and selective A2AR antagonist MSX-3 from 3 to 9-10 months of age. At completion of the treatment, we found that the MSX-3 treatment prevented the development of memory deficits in APP/PS1dE9 mice, without significantly altering hippocampal and cortical gene expressions. Interestingly, MSX-3 treatment led to a significant decrease of Aβ1-42 levels in the cortex of APP/PS1dE9 animals, while Aβ1-40 increased, thereby strongly affecting the Aβ1-42/Aβ1-40 ratio. Together, these data support the idea that A2AR blockade is of therapeutic value for AD.

Highlights

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly
The present study demonstrates that an early, chronic and long-term treatment with a specific A2A receptor (A2AR) antagonist, starting from an asymptomatic stage, prevents spatial memory impairments and reduces, at least in part, the development of amyloidogenesis in APPswe/PS1dE9 mice
Taken together with previous studies demonstrating the ability of A2AR blockade to reduce Tau hyperphosphorylation and associated cognitive decline (Laurent et al, 2016; Zhao et al, 2017), these data support that A2AR signaling is a target of interest in AD

Summary

Introduction

Alzheimer’s disease (AD) is the most common neurodegenerative disorder in the elderly. A2A Receptor Antagonist and Alzheimer’s Disease reported an inverse relation between caffeine intake, age-related cognitive impairments and the risk to develop AD later in life (for reviews see Flaten et al, 2014; Cunha, 2016). We and others have shown that caffeine is beneficial towards memory impairments and pathology in transgenic mouse models of AD (Arendash et al, 2006, 2009; Cao et al, 2009; Laurent et al, 2014). Pharmacological and genetic A2AR blockade was found to reduce hippocampal pathology, neuroinflammation and memory deficits in a model of AD-like Tau pathology (Laurent et al, 2016). The impact of a long-term and chronic A2AR blockade on the development of amyloid pathology and associated memory impairment has not been investigated yet

Methods

Results

Conclusion