New A_2A Receptor Study Offers Insights on Memory Loss Associated with Aging

An international team says it has described a new mechanism involved in memory loss associated with aging. Their study (“Age-Related Shift in LTD Is Dependent on Neuronal Adenosine A_2A Receptors Interplay with mGluR5 and NMDA Receptors”), published in Molecular Psychiatry, shows that specific changes in the signaling of circuits involved in memory induce an abnormal response of the neurons in the brain that is associated with aging. Understanding these processes is crucial in defining new therapeutic strategies as aging is the greatest risk factor for neurodegenerative diseases, according to the scientists.

“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,” write the investigators.

“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.”

The researchers studied the brains of elderly patients and found for the first time that the A_2A adenosine receptor (caffeine target in the brain) is specifically located in neurons. “We already knew that this receptor was increased under these conditions, but little was known about the type of cells in which the receptors would actually be located. We have demonstrated that these receptors are mainly concentrated in neurons, and less in glial cells, at least in elderly patients, ” explains Luísa Lopes, Ph.D., group leader at Instituto de Medicina Molecular João Lobo Antunes (iMM, Portugal).

To better understand its function, the team generated an animal model that reproduces the increase of adenosine receptor in the same brain areas as those observed in patients. The team found that in these neurons, there is an increased release of glutamate, the most abundant neurotransmitter in the brain. Using a combination of electrical records and calcium measurements, it was possible to detect that under these conditions an overactivation of glutamate signaling occurs. “Just by altering the amount of the adenosine receptor in hippocampal and cortex neurons, we induced a profile that we have called early aging, as it causes cognitive deficits and changes in neuronal transmission,” says Mariana Temido, the first author of the study and student of the iMM BioMed Ph.D., program.

“To prove the importance of this finding, we wanted to test if the same mechanism occurs in older animals and not only in our model. On the one hand, we have demonstrated that the overactivation of glutamate receptors is detected in elderly animals. On the other hand, we have shown that the A_2A receptor is indeed involved in this circuit, because when we blocked its action, we normalized both neuronal function and reversed memory deficits,” says Dr. Lopes.

This work opens new perspectives for the design of drugs that regulate this new aberrant signaling, namely the caffeine family that was also tested effectively in the study, she points out, adding that it allows the creation of new models that are useful in the understanding of aging.