The role of A2A receptors in cognitive decline : decoding the molecular shift towards neurodegeneration

Aging is associated with cognitive decline both in humans and animals. Importantly, aging is the main risk factor for nerurodegenerative diseases, namely Alzheimer’s disease (AD), which primarily affects synapses in the temporal lobe and hippocampal formation. In fact, synaptic dysfunction plays a central role in AD, since it drives cognitive decline. Indeed, in age-related neurodegeneration, cognitive decline has a stronger correlation to early synapse loss than neuronal loss in patients. Despite the many clinical trials conducted to identify drug targets that could reduce protein toxicity in AD, such targets and strategies have proven unsuccessful. Therefore, 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. A recent genetic study discovered a significant association of the adenosine A2A receptor encoding gene (ADORA2A) with hippocampal volume in mild cognitive impairment and Alzheimer’s disease. There is compelling evidence from animal models of a cortical and hippocampal upsurge of adenosine A2A receptors (A2AR) in glutamatergic synapses upon aging and AD. Importantly, the blockade of A2AR prevents hippocampus-dependent memory deficits and synaptic impairments in aged animals and in several AD models. Accordingly, 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. Together, these data suggest that A2AR might be a good candidate as trigger to synaptic dysfunction in aging and AD. The main goal of this dissertation was then to explore the synaptic function of A2AR in age-related conditions. We have assessed the A2AR expression in human hippocampal slices and found a significant upsurge of A2AR in hippocampal neurons of aged humans, a phenotype aggravated in AD patients. Increased selective expression of A2AR driven by the CaMKII promoter in rat forebrain neurons was sufficient to mimic aging-like memory impairments, assessed by the Morris water maze task, and to uncover an LTD-to-LTP shift in the Schaffer collaterals-CA1 synapse of hippocampus. This shift was due to an increased NMDA receptor gating and associated to increased Ca2+ influx. The mGluR5-NMDAR interplay was identified as a key event in A2AR-induced synaptic dysfunction. Moreover, chronic treatment with an A2AR selective antagonist, orally delivered for one month, rescued the aberrant NMDAR overactivation and the plasticity shift. Importantly, the same LTD-to-LTP shift was observed in memory-impaired aged rats and APP/PS1 mice modeling AD, a phenotype rescued upon A2AR blockade. These data support a key role for over-active hippocampal A2AR in aging and AD-dependent synaptic and cognitive dysfunction and may underlie the significant genetic association of ADORA2A with AD. Importantly, this newly found interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity