Summary: Depleting the protein ADORA2B from the blood of mice led to faster cognitive decline, decreased auditory processing, and increased brain inflammation.
Research conducted by Qiang et al has discovered a link between a protein in red blood cells and age-related decline in cognitive performance.
Published in the open access journal PLOS Biology on 17th June 2021, the study shows that depleting mouse blood of the protein ADORA2B leads to faster declines in memory, delays in auditory processing, and increased inflammation in the brain.
As life expectancies around the world increase, so are the number of people who will experience age-related cognitive decline. Because the amount of oxygen in the blood also declines with age, the team hypothesized that aging in the brain might be naturally held at bay by adenosine receptor A2B (ADORA2B), a protein on the membrane of red blood cells which is known to help release oxygen from the blood cells so it can be used by the body. To test this idea, they created mice that lacked ADORA2B in their blood and compared behavioral and physiological measures with control mice.
The team found that as the mice got older, the hallmarks of cognitive decline–poor memory, hearing deficits, and inflammatory responses in the brain–were all greater in the mice lacking ADORA2B than in the control mice. Additionally, after experiencing a period of oxygen deprivation, the behavioral and physiological effects on young mice without ADORA2B were much greater than those on normal young mice.
Thus, aging in the brain is naturally reduced by ADORA2B, which helps get oxygen to the brain when needed. Further testing will be needed to determine whether ADORA2B levels naturally decline with age and whether treatment with drugs that activate ADORA2B can reduce cognitive decline in normal mice.
Dr. Xia, the leader of the study, commented “Red blood cells have an irreplaceable function to deliver oxygen to maintain bioenergetics of every single cell within our body. However, their function in age-related cognition and hearing function remains largely unknown. Our findings reveal that the red blood cell ADORA2B signaling cascade combats early onset of age-related decline in cognition, memory and hearing by promoting oxygen delivery in mice and immediately highlight multiple new rejuvenating targets”.
About this cognition research news
Contact: Yang Xia – PLOS
Image: The image is in the public domain
Original Research: Open access.
“Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming” by Yang Xia et al. PLOS Biology
Erythrocyte adenosine A2B receptor prevents cognitive and auditory dysfunction by promoting hypoxic and metabolic reprogramming
Hypoxia drives aging and promotes age-related cognition and hearing functional decline. Despite the role of erythrocytes in oxygen (O2) transport, their role in the onset of aging and age-related cognitive decline and hearing loss (HL) remains undetermined. Recent studies revealed that signaling through the erythrocyte adenosine A2B receptor (ADORA2B) promotes O2 release to counteract hypoxia at high altitude. However, nothing is known about a role for erythrocyte ADORA2B in age-related functional decline.
Here, we report that loss of murine erythrocyte–specific ADORA2B (eAdora2b−/−) accelerates early onset of age-related impairments in spatial learning, memory, and hearing ability. eAdora2b-/- mice display the early aging-like cellular and molecular features including the proliferation and activation of microglia and macrophages, elevation of pro-inflammatory cytokines, and attenuation of hypoxia-induced glycolytic gene expression to counteract hypoxia in the hippocampus (HIP), cortex, or cochlea. Hypoxia sufficiently accelerates early onset of cognitive and cochlear functional decline and inflammatory response in eAdora2b−/− mice.
Mechanistically, erythrocyte ADORA2B-mediated activation of AMP-activated protein kinase (AMPK) and bisphosphoglycerate mutase (BPGM) promotes hypoxic and metabolic reprogramming to enhance production of 2,3-bisphosphoglycerate (2,3-BPG), an erythrocyte-specific metabolite triggering O2 delivery. Significantly, this finding led us to further discover that murine erythroblast ADORA2B and BPGM mRNA levels and erythrocyte BPGM activity are reduced during normal aging.
Overall, we determined that erythrocyte ADORA2B–BPGM axis is a key component for anti-aging and anti-age–related functional decline.