Expression of RbAp48 diminishes with aging, and increased expression in the dentate gyrus improves memory in aged mice. Similarly, infusions of osteocalcin reduce the detrimental effects of aging on memory in mice. Researchers here demonstrate a link between these two approaches, showing that both RbAp48 and osteocalcin operate via BDNF, well known to be associated with cognitive function over the course of aging. This sort of finding is quite common. All cellular mechanisms involve numerous proteins and can thus be influenced at many points. Research groups tend to independently discover various different approaches, and only later are they understood to involve the same underlying targets.
Alzheimer's disease changes the brain in different ways than does age-related memory loss, a milder, though far more common, memory disorder. Alzheimer's disease begins in a part of the brain called the entorhinal cortex, which lies at the foot of the hippocampus. Age-related memory loss, by contrast, begins within the hippocampus itself, in a region called the dentate gyrus.
In 2013, researchers discovered that a deficiency in the RbAp48 protein is a significant contributor to age-related memory loss but not Alzheimer's. Research has shown that RbAp48 levels decline with age, both in mice and in people. This decline can be counteracted; when researchers artificially increased RbAp48 in the dentate gyrus of aging mice, the animals' memories improved. In 2017, the researchers found another way to improve the memories of mice. Infusions of osteocalcin, a hormone normally released by bone cells, had a positive effect on memory.
A new study connects osteocalcin and RbAp48, suggesting that the key driver of the memory improvements lay in the interplay between these molecules. In a series of molecular and behavioral experiments, the team found that RbAp48 controls the expression levels of BDNF and GPR158, two proteins regulated from osteocalcin. This chain of events appears to be critical; if RbAp48 function is inhibited, osteocalcin infusions have no effect on the animals' memory. Osteocalcin needs RbAp48 to kick start the process.
This complex sequence of molecular signals is entirely different from those associated with Alzheimer's disease. These findings also provide further evidence in favor of what may be the best way to stave off, or even treat, age-related memory loss in people: exercise. Studies in mice have shown that moderate exercise, such as walking, triggers the release of osteocalcin in the body. Over time, osteocalcin may make its way to the brain, where it encounters RbAp48. Eventually, this could have a long-term, positive effect on memory and the brain.