In a recent open-access study, scientists at Columbia University have demonstrated that a protein known as RbAp48 crucially interacts with osteocalcin to help preserve memory. The protein, which is present in mice as well as people, declines with age, contributing to age-related memory loss .
Precisely deciphering the molecular mechanisms of age-related memory loss is crucial to create appropriate therapeutic interventions. We have previously shown that the histone-binding protein RbAp48/Rbbp4 is a molecular determinant of Age-Related Memory Loss. By exploring how this protein regulates the genomic landscape of the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of osteocalcin (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation inhibits OCN’s beneficial functions in cognition and causes deficits in discrimination memory. In turn, disruption of OCN/GPR158 signaling leads to the downregulation of RbAp48 protein, mimicking the discrimination memory deficits observed in the aged hippocampus. We also show that activation of the OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues age-related memory loss.
Age-related memory loss
Even relatively healthy older individuals who don’t end up developing Alzheimer’s disease or other neurodegenerative conditions will suffer from age-related memory loss to some degree. While memory loss is certainly a symptom of Alzheimer’s disease, age-related memory loss is different in that it originates in a different part of the brain. As explained by the study’s lead author, Dr. Eric Kandel, Alzheimer’s disease starts at the bottom of the hippocampus, whereas age-related memory loss begins in the dentate gyrus, another area of the hippocampus. Additionally, although Alzheimer’s disease involves an accumulation of unwanted proteins (amyloids), age-related memory loss appears to be driven partly by protein deficiency—that is, low levels of the RbAp48 protein.
Indeed, Dr. Kandel himself showed in a 2013 study that this protein is involved in age-related memory loss but not Alzheimer’s disease and that boosting RbAp48 levels in the dentate gyri of aged mice helped to improve their memory.
The newest study by Dr. Kandel and his team links their 2013 study to a 2017 one about osteocalcin, which was run in collaboration with another research team led by Dr. Gerard Karsenty. Osteocalcin is a hormone secreted by osteoblasts and found in bone and dentin; according to the results of the 2017 study, infusions of osteocalcin also boost the memory of aged mice; however, as the researchers found out recently, osteocalcin and RbAp48 don’t act separately.
The RbAp48 protein controls the expression level of two other proteins: BDNF and GPR158. Both of them are necessary for cognitive functions—particularly, BDNF is heavily involved in neurogenesis—and are regulated by osteocalcin. Thus, osteocalcin and RbAp48 turn out to be two essential ingredients—Dr. Kandel’s team found out that if RbAp48 is inhibited, then infusions of osteocalcin no longer improve the memory of elderly mice.
In addition to providing further evidence of the difference between age-related memory loss and Alzheimer’s, this study points out how exercise—one of the few, proven and cheap ways to ameliorate aging thus far—may help stave off age-related memory loss; indeed, other mouse studies by Dr. Karsenty’s team showed how moderate exercise boosts osteocalcin production, helping to maintain healthy levels of at least one of the two critical components involved in BDNF and GPR158 regulation.
 Kosmidis, S., Polyzos, A., Harvey, L., Youssef, M., Denny, C. A., Dranovsky, A., & Kandel, E. R. (2018). RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss. Cell Reports, 25(4), 959-973.