The definitive diagnosis of Alzheimer’s Disease (AD) is mostly based on the observation of characteristic brain lesions, usually found during post-mortem examination: ß-amyloid deposits and neurofibrillary tangles. Neuro-inflammation, common to most neurodegenerative disorders is also another important hallmark of AD. Neurofibrillary degeneration, found in more than 20 neurodegenerative disorders referred to as Tauopathies, consists of the intraneuronal accumulation of hyper- and abnormally phosphorylated Tau proteins. Compelling evidence indicate that Tau pathology is instrumental in several brain processes driving progressive memory loss in AD.
Modulating Tau phosphorylation/aggregation itself but also associated impairments, as neuro-inflammatory processes and memory defects, is certainly of interest in a therapeutic perspective. With this regards, adenosine A2A receptors (A2AR) are targets to take in consideration. A2ARs are constitutively activated G-protein coupled-receptors, preferentially expressed by the striato-pallidal medium spiny striatal neurons but also hippocampal pyramidal neurons as well as astrocytes and microglial cells.
Recent works support that A2AR blockade is protective against synaptic and astroglial impairments induced acutely by ß-amyloid. Conversely, relationship between A2ARs and the Tau side of AD remained unkown so far. We have recently obtained the first experimental data linking A2AR to Tau pathology. Indeed, global genetic blockade of A2ARs in a Tau transgenic mouse model (THY-Tau22) prevents from development of spatial memory alterations but also significantly reduces neuro-inflammatory processes as well as hippocampal Tau phosphorylation.
On one hand, these data thus give the first proof-of-concept of a positive outcome of A2AR blockade towards Tau-related impairments. From a therapeutic perspective, we thus now need to establish the pre-clinical potential of A2AR blockade using pharmacological approaches. In the present project, we will develop original A2A receptor antagonists of potential therapeutic interest and evaluate their efficacy in THY-Tau22 mice. Indeed, although many efforts have been conducted for the identification of potent antagonist compounds, there is still a need for improving their affinity and selectivity as well as their ADME properties. Efficacy of newly designed antagonist(s) will be compared to the well-characterized xanthine-based antagonist (MSX-3).
On the other hand, our data support that tonic activation of A2ARs is instrumentally involved in the physiopathological development in THY-Tau22 mice. This idea is in line with previous observations showing that A2A receptor expression is increased in the brain of AD patients. However, A2ARs are not only expressed by neurons but also by non-neuronal cells. The respective regulation promoted, in THY-Tau22 mice, by A2ARs located on different cell populations (neuron vs. glia) upon memory, neuro-inflammation and Tau phosphorylation/aggregation is unknown and underlying mechanisms remain to be uncovered. To answer this question, we have developed regulatable models allowing driving A2AR over-expression in a cell- and time-specific manner. These models will be crossed with THY-Tau22 mice to allow modulation of A2AR activity in their forebrain neurons, astrocytes or microglial cells.
Overall, this project will thus establish new therapeutic options in the AD field but also bring important insights on their role in hippocampus and AD physiopathology.
"Alzheimer & Tauopathies", Inserm U837 (Laboratoire public)
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Groupe de Recherche Interdisciplinaire Innovation et Optimisation Thérapeutique
"Alzheimer & Tauopathies", Inserm U837
Aide de l'ANR 407 439 euros
Début et durée du projet scientifique : décembre 2012 - 48 Mois