A study by researchers from the Institute of Molecular Medicine (iMM) in Lisbon, Inserm in Lille and others explored the link between the over-expression of the adenosine A2A receptor (A2AR) and memory problems.
In the rat study, they showed A2AR over-expression disrupted the hypothalamic-pituitary-adrenal feedback system and caused a fall in glucocorticoid receptors – creating brain conditions similar to those in aged rats.
Researchers put transgenic rats - altered to over-express human A2AR - through maze tests. The modified rats performed worse than their wild-type peers, but their performance improved after being treated with anti-A2AR drugs.
Caffeine can bind A2A receptors
Caffeine is known to be an effective A2AR antagonist – the researchers said this latest study demonstrated the specific mechanism through which caffeine helps improve memory function.
“The beneficial effects of A2AR antagonists, namely caffeine, against cognitive impairments may be, at least partially, due to the now reported effects on glucocorticoid receptors,” the researchers wrote in the journal Scientific Reports.
“The expansion of this interaction to the immune response, cell proliferation, tumour response and other cellular functions that imply glucocorticoid receptors or corticosteroids use in therapeutics, could have an enormous clinical impact,” they said.
David Blum, research director at Inserm, said: “In elderly people, we know there is an increase of stress hormones that have an impact on memory. Our work supports the view that the pro-cognitive effects of A2AR antagonists, namely caffeine, observed in Alzheimer's and age-related cognitive impairments may rely on this ability to counteract the loss of stress controlling mechanisms that occurs upon ageing.”
First time A2AR-GR link is documented
This study is the first to confirm the link between increases in A2AR expression in the hippocampus and falls in glucocorticoid receptor density, according to the researchers. Both these conditions have been documented as features of ageing and Alzheimer’s disease.
The researchers said the A2AR-glucocorticoid receptor link has “far-reaching implications” in multiple conditions which can be alleviated by caffeine.
“Various studies also support the ability of caffeine and A2AR blockade to prevent memory impairment in various conditions, and recent work revealed that caffeine can even have pro-cognitive effects.
"A2AR antagonism was also proposed for the treatment of depression and anxiety-like disorders in agreement with the decreased incidence of depression in individuals consuming caffeine,” wrote the researchers.
“These findings are critical, not only for possible treatment strategies of the memory dysfunction associated with psychopathologies, but also in the context of ageing and other circumstances in which the glucocorticoid response is impaired,” they added.
Source: Scientific Reports
Published online ahead of print, doi: 10.1038/srep31493
“The caffeine-binding adenosine A2A receptor induces age-like HPA-axis dysfunction by targeting glucocorticoid receptor function”
Authors: Batalha, V. L. et al