A team of Columbia University Medical Center (CUMC) researchers, led by Nobel laureate Eric R. Kandel, MD, has found that deficiency of a protein called RbAp48 in the hippocampus is a significant contributor to age-related memory loss and that this form of memory loss is reversible.
The study, conducted in postmortem human brain cells and in mice, also offers the strongest causal evidence that age-related memory loss and Alzheimer’s disease are distinct conditions.
The findings were published in the online edition of Science Translational Medicine .
A Major Cause of Age-Related Memory Loss Identified
“Our study provides compelling evidence that age-related memory loss is a syndrome in its own right, apart from Alzheimer’s. In addition to the implications for the study, diagnosis, and treatment of memory disorders, these results have public health consequences,” said Dr. Kandel, who is University Professor & Kavli Professor of Brain Science, co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, director of the Kavli Institute for Brain Science, and senior investigator, Howard Hughes Medical Institute, at CUMC.Dr. Kandel received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.
“Until now, however, no one has been able to identify specific molecular defects involved in age-related memory loss in humans,” said co-senior author Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and director of the Alzheimer’s Research Center at CUMC.The Highlights
To determine whether RbAp48 plays an active role in age-related memory loss, the researchers turned to mouse studies. “The first question was whether RbAp48 is downregulated in aged mice,” said lead author Elias Pavlopoulos, PhD, associate research scientist in neuroscience at CUMC. “And indeed, that turned out to be the case—there was a reduction of RbAp48 protein in the DG.”
In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice. “We were astonished that not only did this improve the mice’s performance on the memory tests, but their performance was comparable to that of young mice,” said Dr. Pavlopoulos.The Conclusions
“The fact that we were able to reverse age-related memory loss in mice is very encouraging,” said Dr. Kandel. “Of course, it’s possible that other changes in the DG contribute to this form of memory loss. But at the very least, it shows that this protein is a major factor, and it speaks to the fact that age-related memory loss is due to a functional change in neurons of some sort. Unlike with Alzheimer’s, there is no significant loss of neurons.”
“Whether these compounds will work in humans is not known,” said Dr. Small. “But the broader point is that to develop effective interventions, you first have to find the right target. Now we have a good target, and with the mouse we’ve developed, we have a way to screen therapies that might be effective, be they pharmaceuticals, nutraceuticals, or physical and cognitive exercises.”
“There’s been a lot of handwringing over the failures of drug trials based on findings from mouse models of Alzheimer’s,” Dr. Small said. “But this is different. Alzheimer’s does not occur naturally in the mouse. Here, we’ve caused age-related memory loss in the mouse, and we’ve shown it to be relevant to human aging.”The paper is titled, “A Molecular Mechanism for Age-Related Memory Loss: The Histone Binding Protein RbAp48.” The other contributors are Sidonie Jones, Stylianos Kosmidis, Maggie Close, Carla Kim, and Olga Kovalerchik, all at CUMC.
The authors declare no financial or other conflicts of interests.
The study was supported by grants from the Howard Hughes Medical Institute, the James S. McDonnell Foundation, the Broitman Foundation, the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc., the McKnight Brain Research Foundation, and the National Institute on Aging (AG034618).
The Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University Medical Center is a multidisciplinary group that has forged links between researchers and clinicians to uncover the causes of Alzheimer’s, Parkinson’s, and other age-related brain diseases and to discover ways to prevent and cure these diseases. For more information, visit The Taub Institute at http://www.cumc.columbia.edu/dept/taub/ .
The Department of Neuroscience at Columbia University Medical Center
CUMC’s Department of Neuroscience, whose faculty includes two Nobel laureates, focuses on fundamental aspects of neural circuit development, organization, and function, using cutting-edge biophysical, cellular imaging, and molecular genetic approaches. Its faculty have backgrounds in a range of fields, including molecular and cell biology, systems neuroscience, theoretical neuroscience, and biophysics.
The Mortimer B. Zuckerman Mind Brain Behavior Institute
Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute is an interdisciplinary center for scholars across the university, created on a scope and scale to explore the human brain and behavior at levels of inquiry from cells to society.
Columbia University Medical Center provides international leadership in basic, preclinical, and clinical research; medical and health sciences education; and patient care. For more information, visit cumc.columbia.edu or columbiadoctors.org .
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