The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function

Abstract

Caffeine is associated with procognitive effects in humans by counteracting overactivation of the adenosine A2A receptor (A2AR), which is upregulated in the human forebrain of aged and Alzheimer’s disease (AD) patients. We have previously shown that an anti-A2AR therapy reverts age-like memory deficits, by reestablishment of the hypothalamic-pituitary-adrenal (HPA) axis feedback and corticosterone circadian levels. These observations suggest that A2AR over-activation and glucocorticoid dysfunction are key events in age-related hippocampal deficits; but their direct connection has never been explored. We now show that inducing A2AR overexpression in an aging-like profile is sufficient to trigger HPA-axis dysfunction, namely loss of plasmatic corticosterone circadian oscillation, and promotes reduction of GR hippocampal levels. The synaptic plasticity and memory deficits triggered by GR in the hippocampus are amplified by A2AR over-activation and were rescued by anti-A2AR therapy; finally, we demonstrate that A2AR act on GR nuclear translocation and GR-dependent transcriptional regulation. We provide the first demonstration that A2AR is a major regulator of GR function and that this functional interconnection may be a trigger to age-related memory deficits. This supports the idea that the procognitive effects of A2AR antagonists, namely caffeine, on Alzheimer’s and age-related cognitive impairments may rely on its ability to modulate GR actions.

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

“…These transgenic rats selectively overexpress the human A 2A R in neurons under the control of the CaMKIIα promoter [Tg(CaMKII-hA 2A R); Fig. 1f], mainly in the cortex and hippocampus, in an aging-like pattern of expression [23,30]. The hippocampus displays a significant overexpression of A 2A R, particularly the DG and CA1, as reported by the in situ A 2A R mRNA human probe ( Fig.…”

“…There is compelling evidence from animal models of a cortical and hippocampal upsurge of A 2A R in glutamatergic synapses upon aging and AD [20][21][22][23][24][25][26]. Such A 2A R overactivation induces glutamate release via PKA/cAMP/CREB signaling [23,25,27,28], calcium influx [29] and leads to hippocampus-dependent cognitive deficits [30,31]. Conversely, the blockade of A 2A R, with either caffeine or more selective antagonists (SCH 58261, KW6002, or MSX-3), prevents hippocampus-dependent memory deficits and LTP impairments in aged animals [32,33] and in several AD models [34][35][36][37].…”

Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption

“…This interaction impacts glucocorticoid receptor-mediated effects on synaptic plasticity, and the blockade of adenosine A 2A receptors by caffeine counteracts the negative effects linked to glucocorticoid receptor function and activation, and this is particularly relevant during stress situations and aging. Whether this interaction also occurs at the level of the immune response, metabolic regulation and other functions remains to be explored (Batalha et al, 2016).…”

Novel Players in the Aging Synapse: Impact on Cognition

“…This idea is further supported by the absence of effect of A 2A R chronic blockade or genetic deletion in the Morris water maze and Y-maze tests. 100,193,195,196 A question might be raised: How could A 2A R behavioral phenotypes, which suggest some memory processes, are upon the control of A 2A R, be reconciled with the absence of an A 2A R constitutive activation in young glutamatergic synapses? Novel mice models with neuronal circuitry/cell type selective A 2A R deletion will allow to dissect which synapses/cells are implicated in the mechanisms underlying these memory phenotypes, excluding artefacts/compensations due to full genetic ablation of the receptor.…”