Malika Hamdane, France
Inserm UMR-S 1172 Lille Neuroscience & Cognition Alzheimer & TauopathiesAuthor Of 1 Presentation
NEURONAL UPREGULATION OF ADENOSINE A2A RECEPTORS EXACERBATES MEMORY DEFICITS IN MOUSE MODELS OF ALZHEIMER'S DISEASE
Abstract
Aims
Alzheimer’s Disease (AD) is characterized by memory loss, underlined by synaptic impairments promoted by both amyloid and Tau lesions. Various studies pointed-out that chronic caffeine consumption reduces Alzheimer's Disease risk and associated cognitive deficits. These protective effects are thought to be ascribed to the blockade of adenosine A2A receptors (A2ARs), known to be crucial for synaptic tuning. Interestingly, A2ARs are found abnormally upregulated in neurons of aged individuals and AD patient’s brains in correlation with the development of cognitive deficits, suggesting a link between neuronal A2AR dysregulation, synapse dysfunction and memory impairments in AD.
Methods
To address the contribution of pathological upsurge of A2AR in AD, we use new transgenic and viral approaches to upregulate neuronal A2AR in the THY-Tau22 model of Tau pathology and the APP/PS1dE9 model of amyloidogenesis. Neuronal upsurge of A2AR was elicited at early pathological stages in both models, at times they do not exhibit memory deficits. These genetic approaches were combined with behavioral, histological, biochemical and molecular (RNA-Seq, mass spectrometry-based high- throughput proteomics) investigations.
Results
Our data revealed that A2AR overexpression worsened AD-related spatial memory impairments without significantly altering Tau and amyloid lesions nor canonical neuroinflammatory markers. Importantly, in both AD models, A2AR-mediated memory impairments were associated with a significant synaptic loss, involving different mechanisms.
Conclusions
These data support that pathological upregulation of A2AR in AD contributes to synaptic and cognitive impairments by differential and convergent pathways paving the way for a therapeutic use of A2AR antagonists.