Summary: Researchers report boosting levels of osteocalcin in the blood may help reverse age related memory loss in mice.
Source: Columbia University Medical Center.
Age-related memory loss may be reversed by boosting blood levels of osteocalcin, a hormone produced by bone cells, according to mouse studies led by Columbia University Medical Center (CUMC) researchers. The research team also identified a receptor for osteocalcin in the brain, paving the way for a novel approach to treating age-related cognitive decline.
The paper was published today in the online edition of the Journal of Experimental Medicine.
“In previous studies, we found that osteocalcin plays multiple roles in the body, including a role in memory,” said study leader Gerard Karsenty, MD, PhD, Paul A. Marks Professor and Chair, Department of Genetics & Development, and Professor of Medicine at CUMC. “We also observed that the hormone declines precipitously in humans during early adulthood. That raised an important question: Could memory loss be reversed by restoring this hormone back to youthful levels? The answer, at least in mice, is yes, suggesting that we’ve opened a new avenue of research into the regulation of behavior by peripheral hormones.”
Karsenty’s group, in collaboration with the laboratory of Eric Kandel, MD, University Professor and Kavli Professor of Brain Science at Columbia University and a key contributor to this study, conducted several experiments to evaluate osteocalcin’s role in age-related memory loss. In one experiment, aged mice were given continuous infusions of osteocalcin over a two-month period. The infusions greatly improved the animals’ performance on two different memory tests, reaching levels seen only in young mice.
The same improvements were seen when blood plasma from young mice, which is rich in osteocalcin, was injected into aged mice. In contrast, there was no memory improvement when plasma from young, osteocalcin-deficient mice was given to aged mice. But adding osteocalcin to this plasma before injecting it into the aged mice resulted in memory improvement. The researchers also used anti-osteocalcin antibodies to deplete the hormone from the plasma of young mice, reducing their performance on memory tests.
The researchers then determined that osteocalcin binds to a receptor called Gpr158 that is abundant in neurons of the CA3 region of the hippocampus, the brain’s memory center. This was confirmed by inactivating hippocampal Gpr158 in mice, and subsequently giving them infusions of osteocalcin, which failed to improve their performance on memory tests.
The researchers did not observe any toxic effects from giving the mice osteocalcin. “It’s a natural part of our body, so it should be safe,” said Dr. Karsenty. “But of course, we need to more research to translate our findings into clinical use for humans.”
In previous research, Dr. Karsenty found that osteocalcin injections also rejuvenate the muscles of older mice, allowing them to match the running speeds and distances of young mice.
“Our laboratory’s long-term interest in the biology of memory and our recent work on age-related memory loss made this a natural collaboration with the Karsenty laboratory, with its background work on osteocalcin,” said Eric Kandel, MD, co-director of the Mortimer B. Zuckerman Mind Brain Behavior Institute at Columbia and a senior investigator at the Howard Hughes Medical Institute. Dr. Kandel was awarded a share of the 2000 Nobel Prize in Physiology or Medicine for his studies of the molecular basis of learning and memory.
The study is titled, “Gpr158 mediates osteocalcin’s regulation of cognition.” The other contributors are: Lori Khrimian (CUMC), Arnaud Obri (CUMC), Mariana Ramos-Brossier (Institut Necker-Enfants Malades, France Institut National de la Santé et de la Recherche Médicale, France Université Paris Descartes, Sorbonne Paris Cité, France), Audrey Rousseaud (Institut Necker-Enfants Malades, France Institut National de la Santé et de la Recherche Médicale, and France Université Paris Descartes, Sorbonne Paris Cité), Stéphanie Moriceau (Institut Necker-Enfants Malades, France Institut National de la Santé et de la Recherche Médicale, and France Université Paris Descartes, Sorbonne Paris Cité), Anne-Sophie Nicot (Grenoble Institute des Neurosciences and INSERM, Grenoble, France), Paula Mera (CUMC), Stylianos Kosmidis (CUMC), Theodoros Karnavas (CUMC), Frederic Saudou (Grenoble Institute des Neurosciences, INSERM, and CHU Grenoble Alpes), Xiao-Bing Gao (Yale University School of Medicine), and Franck Oury (Institut Necker-Enfants Malades).
Funding: This work was supported by grants from the National Institutes of Health (2P01 AG032959-06A1), the Columbia Aging Center, Fondation pour la Recherche Medicale, Human Frontier Scientific Program, Philippe Foundation, and the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
Source: Lucky Tran – Columbia University Medical Center
Image Source: NeuroscienceNews.com image is credited to Schöll et al./Brain.
Original Research: Abstract for “Gpr158 mediates osteocalcin’s regulation of cognition” by Lori Khrimian, Arnaud Obri, Mariana Ramos-Brossier, Audrey Rousseaud, Stéphanie Moriceau, Anne-Sophie Nicot, Paula Mera, Stylianos Kosmidis, Theodoros Karnavas, Frederic Saudou, Xiao-Bing Gao, Franck Oury, Eric Kandel, and Gerard Karsenty in Journal of Experimental Medicine. Published online August 29 2017 doi:10.1084/jem.20171320
Gpr158 mediates osteocalcin’s regulation of cognition
That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein–coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN’s regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes.
“Gpr158 mediates osteocalcin’s regulation of cognition” by Lori Khrimian, Arnaud Obri, Mariana Ramos-Brossier, Audrey Rousseaud, Stéphanie Moriceau, Anne-Sophie Nicot, Paula Mera, Stylianos Kosmidis, Theodoros Karnavas, Frederic Saudou, Xiao-Bing Gao, Franck Oury, Eric Kandel, and Gerard Karsenty in Journal of Experimental Medicine. Published online August 29 2017 doi:10.1084/jem.20171320