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At age of hippocampal signaling pathway improved in rodents



Dentate Gyrus from the brain of a mouse. Credit: Stylianos Kosmidis / Kandel Laboratory / Colombia's Zuckerman Institute

Columbia scientists reveal new details of how a naturally occurring hormone can boost the memory of aging mice and thus lay the groundwork for warding off this form of memory loss in humans

Columbia's study on mice has revealed new details of how a naturally occurring bone hormone reverses memory loss in the aging brain. These findings about the hormone, called osteocalcin, will trigger further research on the molecular machinery underlying memory, and how it can be manipulated to improve it. The research also provides new insights into how lifestyle changes that affect the body, such as exercise, could positively affect the brain.

These findings were reported today by a team of Columbia researchers led by Nobel Laureate Eric R. Kandel, MD, in Cell Reports .

"Almost everyone will experience age-related memory loss throughout their lives, so understanding their causes and finding ways to alleviate them is incredibly important," Dr. Kandel. He is a University Professor and Kavli Professor of Brain Research and Co-Director of Columbia Mortimer B. Zuckerman's Mind Brain Behavior Institute. "With today's study, we not only build a detailed understanding of how age-related memory loss occurs in the brain, but we also demonstrated how osteocalcin interacts with key proteins in the brain to strengthen memory."

This term suggests another line of investigation that we want to explore, how does the aging body affect the aging brain and how can it be reversed?

Memory loss was treated as a singular disorder for many years. Then scientists began to realize that not all forms of memory loss are the same.

Alzheimer's disease changes the brain in different ways, as age-related memory loss, a milder, albeit widespread, memory disorder. While both Alzheimer's and age-related memory loss affect the hippocampus, the brain's brain for learning and memory, each one targets a completely different area within that region.

"Alzheimer's disease begins in one part of the brain, the entorhinal cortex is located at the foot of the hippocampus," said Drs. Kandel, who also works at the Howard Hughes Medical Institute. "Age-related memory loss begins in the hippocampus itself, in a region called gyrus dentatus."

Dr. Kandel and his team discovered in 201

3 another difference between the two diseases: a deficiency of RbAp48 protein is a major contributor to age-related memory loss, but not to Alzheimer's. Research has shown that RbAp48 levels decrease with age in both mice and humans. This decline can be counteracted, the researchers found; when they artificially raised RbAp48 in the dentate gyrus of aging mice, the animals' memories improved.

In 2017, researchers found another way to improve the memory of mice. In collaboration with Gerard Karsenty, MD, PhD, the Paul A. Marks Professor, and the Department of Genetics and Development at Irving Medical Center, Columbia University, the researchers found that osteocalcin, a hormone normally released by bone cells, has a high molecular weight has a positive effect on memory

Today's study combines osteocalcin and RbAp48, suggesting that the key factor in improving memory is the interaction of 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 by osteocalcin. This chain of events seems critical; When RbAp48 function is inhibited, osteocalcin infusions have no effect on the memory of the animals. Osteocalcin needs RbAp48 to start the process.

This complex sequence of molecular signals is fundamentally different from those associated with Alzheimer's disease. "This is the clearest evidence that age-related memory loss and Alzheimer's are clear diseases," Dr. Kandel.

These results also provide further evidence of what the best way is to ward off or even treat age-related memory loss in humans: exercise. Studies on mice by Dr. med. Karsenty's team has shown that moderate exercise, such as walking, triggers the release of osteocalcin in the body. Dr. Kandel suggests that over time, osteocalcin could find its way to the brain where it encounters RbAp48. This could have long-term positive effects on the memory and the brain.

"This notion points to another type of investigation we want to explore, how does the aging body affect the aging brain, and how can it be reversed?" Kandel, "Our latest findings are almost certainly not the whole story, they're just the beginning."

This article was re-released from Columbia University materials in the city of New York. Note: Material may have been edited for length and content. For more information, please contact the cited source.

Reference:

Kosmidis, S., Polyzos, A., Harvey, L., Youssef, M., Denny, CA, Dranovsky, A., & Kandel, ER (2018). RbAp48 protein is a critical component of GPR158 / OCN signaling and improves age-related memory loss. Cell Reports, 25 (4). doi: 10.1016 / j.celrep.2018.09.077


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