Alzheimer's disease (AD) is characterized by memory impairment, neurochemically by accumulation of β-amyloid peptide (namely Aβ_1-42) and morphologically by an initial loss of nerve terminals. Caffeine consumption prevents memory dysfunction in different models, which is mimicked by antagonists of adenosine A_2Areceptors (A_2ARs), which are located in synapses. Thus, we now tested whether A_2AR blockade prevents the early Aβ_1-42-induced synaptotoxicity and memory dysfunction and what are the underlying signaling pathways. The intracerebral administration of soluble Aβ_1-42(2 nmol) in rats or mice caused, 2 weeks later, memory impairment (decreased performance in the Y-maze and object recognition tests) and a loss of nerve terminal markers (synaptophysin, SNAP-25) without overt neuronal loss, astrogliosis, or microgliosis. These were prevented by pharmacological blockade [5-amino-7-(2-phenylethyl)-2-(2-furyl)-pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH58261); 0.05 mg · kg⁻¹· d⁻¹, i.p.; for 15 d] in rats, and genetic inactivation of A_2ARs in mice. Moreover, these were synaptic events since purified nerve terminals acutely exposed to Aβ_1-42(500 nm) displayed mitochondrial dysfunction, which was prevented by A_2AR blockade. SCH58261 (50 nm) also prevented the initial synaptotoxicity (loss of MAP-2, synaptophysin, and SNAP-25 immunoreactivity) and subsequent loss of viability of cultured hippocampal neurons exposed to Aβ_1-42(500 nm). This A_2AR-mediated control of neurotoxicity involved the control of Aβ_1-42-induced p38 phosphorylation and was independent from cAMP/PKA (protein kinase A) pathway. Together, these results show that A_2ARs play a crucial role in the development of Aβ-induced synaptotoxicity leading to memory dysfunction through a p38 MAPK (mitogen-activated protein kinase)-dependent pathway and provide a molecular basis for the benefits of caffeine consumption in AD.

Significance: Epidemiological studies show that individuals exposed to repeated stress, a major trigger of depression, increase their caffeine intake, which correlates inversely with the incidence of depression. However, the mechanism underlying this protective effect is unknown. We used an animal model of chronic unpredictable stress (CUS) to show that caffeine prevents the maladaptive changes caused by CUS in a manner mimicked by the selective blockade of adenosine A _2A receptors (A _2A R). CUS enhanced A _2A R in synapses, and the selective elimination of neuronal A _2A R abrogated CUS modifications. Moreover, A _2A R blockade also afforded a therapeutic benefit, paving the way to consider A _2A R blockers as a strategy to manage the negative impact of chronic stress on mood and memory.

Synaptic dysfunction plays a central role in Alzheimer’s disease (AD), since it drives the cognitive decline. An association between a polymorphism of the adenosine A_2A receptor (A_2AR) encoding gene—ADORA2A, and hippocampal volume in AD patients was recently described. In this study, we explore the synaptic function of A_2AR in age-related conditions. We report, for the first time, a significant overexpression of A_2AR in hippocampal neurons of aged humans, which is aggravated in AD patients. A similar profile of A_2AR overexpression in rats was sufficient to drive age-like memory impairments in young animals and to uncover a hippocampal LTD-to-LTP shift. This was accompanied by increased NMDA receptor gating, dependent on mGluR5 and linked to enhanced Ca²⁺ influx. We confirmed the same plasticity shift in memory-impaired aged rats and APP/PS1 mice modeling AD, which was rescued upon A_2AR blockade. This A_2AR/mGluR5/NMDAR interaction might prove a suitable alternative for regulating aberrant mGluR5/NMDAR signaling in AD without disrupting their constitutive activity.