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Memory dysfunction on ageing is blunted by caffeine – role of adenosine A2A receptor antagonists

Rodrigo Cunha (1, 2, 3)

  1. CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Portugal

  2. MIA-Multidisciplinary Institute of Ageing, University of Coimbra, Portugal

  3. Faculty of Medicine, University of Coimbra, Portugal

Coffee is the most consumed beverage worldwide and seems to contribute for a healthy ageing. In fact, the regular consumption of moderate doses of coffee is associated with increased longevity and healthspan, supporting that coffee intake should be part of a healthy life-long diet. One particular component of coffee has been shown to attenuate neuropsychiatric diseases such as memory deficits and mood deterioration through its ability to rebalance a modulation system operated by adenosine.

The adenosine neuromodulation system mostly operates through inhibitory A1 (A1R) and facilitatory A2A receptors (A2AR). The activity-dependent release of adenosine acts as a brake of excitatory transmission through A1R, which are enriched in glutamate terminals. Adenosine actually sharpens salience of information encoding in neuronal circuits: high-frequency stimulation triggers ATP release in ‘activated’ synapses; ATP is locally converted by ecto-nucleotidases into adenosine to selectively activate A2AR; A2AR switch off A1R and CB1R, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in ‘activated’ synapses; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change.

The adenosine system in the brain is modified upon aging: there is a decrease density and efficiency of inhibitory A1R in parallel with an increased density and efficiency of A2AR, observed both in rodents and in humans. The over-activation of hippocampal A2AR is actually sufficient to trigger memory impairment, as shown both upon pharmacological activation of A2AR or opto-activation of the A2AR transducing system in the hippocampus during performance of spatial memory tasks (collaboration with Jiang Fan Chen). This A2AR over-activation seems to be a hallmark of brain diseases involving memory dysfunction, such as Alzheimer’s disease, epilepsy, depression, ADHD or diabetic encephalopathy, probably as an attempt to bolster synaptic stability, which is a key role of A2AR during development (collaboration with Sabine Levi and Christophe Bernard).

This prompts the proposal that the over-functioning of hippocampal A2AR might actually be responsible for memory impairment upon aging. In accordance with this contention, A2AR blockade restores the abnormal hippocampal long-term potentiation (LTP) upon aging and an LTD-to-LTP shift characteristic of memory impairment upon aging (collaboration with Luisa V. Lopes). Furthermore, both the regular intake of caffeine (a non-selective adenosine receptor antagonist) and selective A2AR antagonists restore the performance of reference spatial memory in aged mice and rats.

Overall, these observations herald the concept that adenosine A2AR over-function might be a critical contributing factor for memory deterioration associated with aging, as well as for the greater susceptibility of brain diseases in the elderly. Furthermore, this imbalance of the adenosine modulation system upon aging also provides a rationale to understand the particular ability of caffeine to normalize mood and memory performance in aged compared to younger adult subjects and prompts the suggestions that: i) A2AR polymorphisms might be predictors of memory deterioration upon aging; ii) PET analysis of A2AR density might be an ancillary biomarker of memory function upon aging; iii) A2AR antagonists might be of particular interest as cognitive bolsters in aged individuals.