Re: [GRG] Age-related memory loss / potential target

Contact: Karin Eskenazi
ket2116@columbia.edu
212-342-0508
Columbia University Medical Center

A major cause of age-related memory loss identified
Study points to possible treatments and confirms distinction
between memory loss due to aging and that of Alzheimer’s

IMAGE: The researchers have identified a protein—RbAp48—that, when
increased in aged wild-type mice, improves memory back to that of
young wild-type mice. In the image, yellow shows the increased
RbAp48 in…

Click here for more information.

NEW YORK, NY (August 28, 2013) — 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 today in the online edition of Science Translational
Medicine.

“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.

The hippocampus, a brain region that consists of several
interconnected subregions, each with a distinct neuron population,
plays a vital role in memory. Studies have shown that Alzheimer’s
disease hampers memory by first acting on the entorhinal cortex
(EC), a brain region that provides the major input pathways to the
hippocampus. It was initially thought that age-related memory loss
is an early manifestation of Alzheimer’s, but mounting evidence
suggests that it is a distinct process that affects the dentate
gyrus (DG), a subregion of the hippocampus that receives direct
input from the EC.

“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 current study was designed to look for more direct evidence
that age-related memory loss differs from Alzheimer’s disease. The
researchers began by performing microarray (gene expression)
analyses of postmortem brain cells from the DG of eight people,
ages 33 to 88, all of whom were free of brain disease. The team
also analyzed cells from their EC, which served as controls since
that brain structure is unaffected by aging. The analyses
identified 17 candidate genes that might be related to aging in the
DG. The most significant changes occurred in a gene called RbAp48,
whose expression declined steadily with aging across the study
subjects.

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.”

When the researchers genetically inhibited RbAp48 in the brains of
healthy young mice, they found the same memory loss as in aged
mice, as measured by novel object recognition and water maze memory
tests. When RbAp48 inhibition was turned off, the mice’s memory
returned to normal.

VIDEO: A team of Columbia University Medical Center researchers,
led by Nobel laureate Eric R. Kandel, MD, has found that deficiency
of a protein called RbAp48 in the hippocampus is a…

Click here for more information.

The researchers also did functional MRI (fMRI) studies of the mice
with inhibited RbAp48 and found a selective effect in the DG,
similar to that seen in fMRI studies of aged mice, monkeys, and
humans. This effect of RbAp48 inhibition on the DG was accompanied
by defects in molecular mechanisms similar to those found in old
mice. The fMRI profile and mechanistic defects of the mice with
inhibited RbAp48 returned to normal when the inhibition was turned
off.

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 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.”

Finally, the study data suggest that RbAp48 protein mediates its
effects, at least in part, through the PKA-CREB1-CBP pathway, which
the team had found in earlier studies to be important for age-
related memory loss in the mouse. According to the researchers,
RbAp48 and the PKA-CREB1-CBP pathway are valid targets for
therapeutic intervention. Agents that enhance this pathway have
already been shown to improve age-related hippocampal dysfunction
in rodents.

“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.

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About Johnny Adams

My full-time commitment is to slow and ultimately reverse age related functional decline to increase healthy years of life. I’ve been active in this area since the 1970s, steadily building skills and accomplishments. I have a good basic understanding of the science of aging, and have many skills that complement those of scientists so they can focus on science to advance our shared mission. Broad experience Top skills: administration, management, information technology (data and programming), communications, writing, marketing, market research and analysis, public speaking, forging ethical win-win outcomes among stakeholders (i.e. high level "selling"). Knowledge in grant writing, fundraising, finance. Like most skilled professionals, I’m best described as a guy who defines an end point, then figures out how to get there. I enjoy the conception, design, execution and successful completion of a grand plan. Executive Director Gerontology Research Group (GRG). Manages Email discussion forum, web site, meetings and oversees supercentenarian (oldest humans, 110+ years) research. CEO / Executive Director Carl I. Bourhenne Medical Research Foundation (Aging Intervention Foundation), an IRS approved 501(c)(3) nonprofit. http://www.AgingIntervention.org Early contributor to Supercentenarian Research Foundation. Co-Founder Geroscience Healthspan Forum. Active contributor to numerous initiatives to increase healthy years of life. Co-authored book on conventional, practical methods available today to slow the processes of aging – nutrition, exercise, behavior modification and motivation, stress reduction, proper supplementation, damage caused by improper programs, risk reduction and others. Fundamental understanding of, and experience in the genomics of longevity (internship analyzing and curating longevity gene papers). Biological and technical includes information technology, software development and computer programming, bioinformatics and protein informatics, online education, training programs, regulatory, clinical trials software, medical devices (CAT scanners and related), hospital electrical equipment testing program. Interpersonal skills – good communication, honest, well liked, works well in teams or alone. Real world experience collaborating in interdisciplinary teams in fast paced organizations. Uses technology to advance our shared mission. Education: MBA 1985 University of Southern California -- Deans List, Albert Quon Community Service Award (for volunteering with the American Longevity Association and helping an elderly lady every other week), George S. May Scholarship, CA State Fellowship. BA psychology, psychobiology emphasis 1983 California State University Fullerton Physiological courses as well as core courses (developmental, abnormal etc). UCLA Psychobiology 1978, one brief but fast moving and fulfilling quarter. Main interest was the electrochemical basis of consciousness. Also seminars at the NeuroPsychiatric Institute. Other: Ongoing conferences, meetings and continuing education. Aging, computer software and information technology. Some molecular biology, biotech, bio and protein informatics, computer aided drug design, clinical medical devices, electronics, HIPAA, fundraising through the Assoc. of Fundraising Professionals. Previous careers include: Marketing Increasing skill set and successes in virtually all phases, with valuable experience in locating people and companies with the greatest need and interest in a product or service, and sitting across the table with decision makers and working out agreements favorable to all. Information Technology: Management, data analysis and programming in commercial and clinical trials systems, and bioinformatics and protein informatics. As IT Director at Newport Beach, CA based technology organization Success Family of Continuing Education Companies, provided online software solutions for insurance and financial professionals in small to Fortune 500 size companies. We were successful with lean team organization (the slower moving competition was unable to create similar software systems). Medical devices: At Omnimedical in Paramount CA developed and managed quality assurance dept. and training depts. for engineers, physicians and technicians. Designed hospital equipment testing program for hospital services division. In my early 20’s I was a musician, and studied psychology and music. Interned with the intention of becoming a music therapist. These experiences helped develop valuable skills used today to advance our shared mission of creating aging solutions.
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