Consumption of caffeine, a non-selective adenosine A_2A receptor (A_2AR) antagonist, reduces the risk of developing Alzheimer’s disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A_2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A_2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A_2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A_2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A_2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A_2A receptors as important molecular targets to consider against AD and Tauopathies.

Systemic or intracerebral administration of glucocorticoids enhances memory consolidation in several tasks. Previously, we reported that these effects depend on an intact basolateral nucleus of the amygdala (BLA) and efferents from the BLA that run through the stria terminalis (ST). The BLA projects directly to the nucleus accumbens (NAc) via this ST pathway. The NAc also receives direct projections from the hippocampus and, therefore, may be a site of convergence of BLA and hippocampal influences in modulating memory consolidation. In support of this view, we found previously that lesions of either the NAc or the ST also block the memory-modulatory effect of systemically administered glucocorticoids. The present experiments examined the effects of lesions of the NAc or the ST on the memory-modulatory effects of intracerebral glucocorticoids on inhibitory avoidance training. Microinfusions of the specific glucocorticoid receptor agonist 11β,17β-dihydroxy-6,21-dimethyl-17α-pregna-4,6-trien-20yn-3-one (RU 28362; 1.0 or 3.0 ng) into either the BLA or the hippocampus of male Sprague Dawley rats administered immediately after training enhanced the 48 hr retention performance in a dose-dependent manner. Bilateral lesions of the NAc or the ST alone did not affect retention performance but blocked the memory enhancement induced by intra-BLA or intrahippocampal glucocorticoid receptor agonist administration. These findings indicate that the BLA–NAc pathway plays an essential role in mediating glucocorticoid effects on memory consolidation and suggest that the BLA interacts with hippocampal effects on memory consolidation via this pathway.