Two things that we often associate with the normal human aging process are bone loss and memory loss. In a remarkable development, research in the Columbia University laboratories of Nobel laureate Eric Kandel, M.D. and colleagues has recently pointed to a possible connection between the two. Although still in its early phases, this research now “paves the way” for the development and testing of a new therapeutic strategy to combat age-related memory loss, according to Dr. Kandel, a Foundation Scientific Council member, and his collaborator Gerard Karsenty, M.D., who chairs the Department of Genetics & Development at Columbia.

It’s important to clarify the distinction between age-related memory loss, which is a normal part of aging, and pathologies of the brain such as Alzheimer’s disease, which affect only a fraction of people. In any group of 100 randomly selected 70-year-olds, Dr. Kandel explains, about 40 will exemplify “successful aging.” They will have memory skills comparable to what they had in their forties. The remaining 60 people will divide in two additional groups. About 30 of these 60 people will already be showing signs of mild age-related memory loss. This condition is normal, and may become more acute as the years pass. It typically involves forgetting people’s names or where one has placed the house keys. The other 30 people will already be on a biological path that will lead to Alzheimer’s disease, assuming their lives are not shortened by other illnesses.

The recent discoveries of Drs. Kandel and Karsenty have relevance to people affected by normal age-related loss of memory. The biological factor their labs have identified that involves both bones and memory is called osteocalcin. It’s a well-known protein, a hormone manufactured in the bones that Dr. Karsenty has found to be involved in promoting the production of insulin in the pancreas, testosterone in the testes, and certain neurotransmitters in the brain. Osteocalcin is produced by cells called osteoblasts, which form groups of connected cells that join together to form new bone tissue. As people get older, bone mass decreases, so does the activity of osteoblasts and bodily levels of osteocalcin. Dr. Karsenty has begun to explore the idea of supplementing osteocalcin in bone tissue in the hope that it will restore bone mass during the aging process.

Over the last several years, Drs. Kandel and Karsenty and their colleagues have pursued an analogous line of investigation in mice to test osteocalcin’s role in memory. This was not a shot in the dark, but rather, research that followed upon the 2013 discovery by Dr. Karsenty that the formation of memory in the brain’s hippocampus cannot occur unless osteocalcin is present. Mice that were unable to make osteocalcin were also observed to have anxiety symptoms, suggesting other functions for the hormone in the brain.

In the Journal of Experimental Medicine in August 2017, Drs. Kandel, Karsenty, and their colleagues reported their discovery of a neuronal receptor – a docking port – where osteocalcin binds. Called Gpr158, this receptor was found to be abundant in neurons located in a layer of the hippocampus called the CA3 region, an area critical in the formation of memory.

The Karsenty team did a wide range of experiments to determine osteocalcin’s role in memory. In one experiment, aged mice were given continuous infusions of osteocalcin over two months, during which time their performance on two different kinds of memory tests not only improved but reached levels seen only in young mice. Similar improvements were noted when blood plasma sampled from young mice – rich in osteocalcin – was injected into another group of aged mice.

The team then performed the blood plasma experiment using plasma drawn from young mice that were unable to manufacture osteocalcin. This time, the aged mice receiving the plasma didn’t improve on memory tests. But when the Karsenty and Kandel labs added osteocalcin to osteocalcindeficient plasma prior to injection into aged mice, this time the recipients’ memory performance was boosted. Finally, the researchers used an antibody to disable osteocalcin in young mice, and then observed the animals’ performance on memory tests. They did poorly.

After discovering Gpr158, the cellular receptor for osteocalcin, the team did one additional experiment, blocking the receptor and then giving mice infusions of osteocalcin. These mice, not surprisingly, had no memory benefit from the injections.

Taken together, this evidence is impressive, Dr. Kandel says. He notes that unlike some proteins, osteocalcin can cross the blood-brain barrier, and we know that it targets a specific receptor in brain cells – importantly, he says, “in an area of the brain that is involved in age-related memory loss.” The experiments reported in August “show in some detail that giving osteocalcin to aged mice reverses age-related memory loss.”

Whether osteocalcin is alone responsible for normal loss of memory in the aging brain is still not possible to say, Dr. Kandel cautions. It’s true that it is manufactured in our bones, and we know that its level drops off after early adulthood. “But there may be other reasons for memory loss that we don’t know.”

“We now hope to make an arrangement with a pharmaceutical company that would develop a drug based on the concept,” Dr. Kandel says. “We would of course need to get FDA approval to do clinical trials, etc. But you know, it’s a long road ahead. Drug development is never easy or straightforward.”

Dr. Kandel, Dr. Karsenty, and their team noted in their August paper that no toxic effects of osteocalcin injection or infusion were noted in mice – but added that “of course we need to do more research to translate our findings into clinical use for humans.”

Since osteocalcin is a protein, it has to be delivered via injection; one possible objective of a pharmaceutical developer would be to invent an analog compound that could be given as a pill. This would make its potential use as a drug for people much more practical, should it prove to benefit aging people as it appears to benefit aging mice.

DR. KANDEL’S RESEARCH TAKES A THERAPEUTIC TURN

“When I talk at various seminars and meetings about our recent research on osteocalcin and age-related memory loss, the attention it gets is remarkable,” Dr. Eric Kandel reports. His career has included some of the most important discoveries of modern neuroscience; his Nobel Prize in 2000 recognized decades of his research that helped to establish the molecular basis of memory. This long record of achievement has taught Dr. Kandel the virtue of not assuming too much about research that is still in its early stages, no matter how encouraging. And this, he stresses, is where the osteocalcin research stands today.

“Memory loss is so urgent a public health issue,” he notes, that any suggestion of progress in combating it will naturally raise expectations. He hopes, of course, that the new research is opening a productive path. “Look – I’m 88,” he says. “I wouldn’t mind having a drug of this type around! It’s potentially very useful. But the difference between ‘potential’ and ‘definitive’ is a big step.”

While he is cautious about where the osteocalcin research will lead, Dr. Kandel is quick to say that he is “very excited that at this point in my career, I have a completely new and interesting direction in my work!”

In fact, the research on age-related memory loss is only part of a broader contribution his lab has made to neuroscience since 2010. Kandel thinks “one of the most important things to have emerged” from his group is research that pertains to Alzheimer’s and other pathological conditions that devastate human memory – in contrast to the slow and comparatively mild deterioration that accompanies normal aging.

Pharmaceutical companies have spent– and lost – billions of dollars over the last decade in efforts, so far unsuccessful, to develop and test drugs designed to break up the plaque-like clumps of material whose toxic accumulation is seen in the brains of Alzheimer’s patients, as well as people with other neurodegenerative illnesses such as Parkinson’s and Huntington’s diseases. Several theories have evolved to explain these pathologies. Some focus on clumps of amyloid-beta protein as the culprit in Alzheimer’s. Molecules called apolipoproteins normally break down clumps such as those formed by amyloid-beta, and a faulty variant of one such molecule, made by a gene variant called APOE4, is thought to contribute to the pathology. Others have studied the possible contribution of faulty tau proteins, which can form tangles and disrupt brain structure.

Protein aggregation is commonly associated with pathology, in part because of the role played in certain degenerative illnesses by prions. Prions are proteins that assemble into clumps and spread like an infection, wreaking havoc. But in recent years, Dr. Kandel’s lab has made a major contribution to the discussion by proving something highly counterintuitive. They’ve shown that protein clumping or aggregation in the brain can also perform a vital role in normal brain function.

“The preponderance of amyloid-based illnesses in the central nervous system of man may reflect the presence of prions in the nervous system serving normal functions,” Dr. Kandel has written. In other words, prions help the body – including the brain – do various important things, so long as they are properly regulated.

A flurry of papers suggesting a positive role for prions in the brain has been published by Kandel and colleagues since 2015. They have shown that a protein called CPEB3 has a necessary role in synaptic plasticity and memory – specifically, in the stabilization of long-term memory. The protein, in prion-like fashion, forms aggregates or clumps in the brain’s hippocampus after synapses (tiny gaps across which neighboring neurons communicate) have been activated, the initial step in the formation of a memory.

Some memories are short-term; they last a few hours, but pass out of memory when the synapses that contain their information are re-shaped. To retain a memory for a long time – days, months, years, or a lifetime – the brain needs a mechanism that stabilizes a given configuration of synapses and preserves it indefinitely. But how?

Dr. Kandel and colleagues discovered the astonishing fact that CPEB3 (one of several variants of the CPEB protein) uses a prion-like mechanism to stabilize and preserve long-term memory in the hippocampus. When these neurons are stimulated, CPEB3 is transformed from an inactive form, in which individual CPEB3 proteins exist as single molecules, into an active form in which they clump together and begin to promote the activation of RNA messages copied from genes. These are blueprints that neurons use to manufacture other proteins involved in memory preservation. The clumping or aggregation of the CPEB3 proteins thus sets off the process through which memory traces at synapses are stabilized and preserved.

In discovering this mechanism, Dr. Kandel and colleagues also gained insight into how helpful prions can be kept under control. When CPEB3 is in its inactive state, it doesn’t form clumps. This is because it interacts with a protein called SUMO. When a long-term memory is formed, CPEB3 must be “de-SUMOylated,” to use the scientists’ terminology, so that it can form aggregates with other CPEB3 proteins. The clumping, in other words, is context- specific, associated specifically with memory stabilization.

Dr. Kandel, apart from being thrilled at the relevance of this new work, notes with interest that it is “moving, increasingly, in a therapeutic direction.”

“Now, on the one hand, that’s very pleasing,” he says. “I’m trained as a psychiatrist and I’ve been working on basic research involving marine snails and things like that! [His early work explained how the marine snail called Aplysia californica is able to learn and remember, based on its experiences.] It’s nice to think I’m working on things that pertain directly to clinical medicine.”

“But I also think this is about something much, much deeper. And that is that molecular biology has become so powerful and all-encompassing that its ability to address a range of problems, including therapeutic ones, has increased. Some of the things we can do now were inconceivable even 10 years ago. The power of science – the kind of science that the Foundation funds every year – has matured. All of this is supposed to lead to therapeutics, and in a number of cases, it’s beginning to do that!”

— Written By Peter Tarr, Ph.D.

Click here to read the Brain & Behavior Magazine's March 2018 issue