Researchers identify major cause of age-related memory loss

August 28, 2013
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 the dentate gyrus. Credit: Elias Pavlopoulos, Ph.D./Columbia University Medical Center

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 is a syndrome in its own right, apart from Alzheimer's. In addition to the implications for the study, diagnosis, and treatment of , 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 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."

The video will load shortly
Credit: Columbia University Medical Center

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.

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 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 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."

Explore further: Study identifies protein that contributes to cognitive decline in Alzheimer's

More information: "A Molecular Mechanism for Age-Related Memory Loss: The Histone Binding Protein RbAp48" Science Translational Medicine, 2013.

Related Stories

Study identifies protein that contributes to cognitive decline in Alzheimer's

June 25, 2013
Researchers at Columbia University Medical Center (CUMC) have demonstrated that a protein called caspase-2 is a key regulator of a signaling pathway that leads to cognitive decline in Alzheimer's disease. The findings, made ...

Innovative method to treat Alzheimer's in mice

April 1, 2013
Researchers from the RIKEN Brain Science Institute report that they successfully used a virus vector to restore the expression of a brain protein and improve cognitive functions, in a mouse model of Alzheimer's disease.

Brain enzyme is double whammy for Alzheimer's disease

August 20, 2012
The underlying causes of Alzheimer's disease are not fully understood, but a good deal of evidence points to the accumulation of β-amyloid, a protein that's toxic to nerve cells. β-amyloid is formed by the activity ...

A lifespan-extending drug has limited effects on aging

July 25, 2013
The immunosuppressive drug rapamycin has been shown to increase longevity in mice even when treatment begins at an advanced age. It is unclear if the extension of life also correlates with prolonged health and vigor.

Reducing caloric intake delays nerve cell loss

May 21, 2013
Activating an enzyme known to play a role in the anti-aging benefits of calorie restriction delays the loss of brain cells and preserves cognitive function in mice, according to a study published in the May 22 issue of The ...

Neuroscientists identify protein linked to Alzheimer's-like afflictions

August 11, 2013
A team of neuroscientists has identified a modification to a protein in laboratory mice linked to conditions associated with Alzheimer's Disease. Their findings, which appear in the journal Nature Neuroscience, also point ...

Recommended for you

The neural codes for body movements

July 21, 2017
A small patch of neurons in the brain can encode the movements of many body parts, according to researchers in the laboratory of Caltech's Richard Andersen, James G. Boswell Professor of Neuroscience, Tianqiao and Chrissy ...

Faulty support cells disrupt communication in brains of people with schizophrenia

July 20, 2017
New research has identified the culprit behind the wiring problems in the brains of people with schizophrenia. When researchers transplanted human brain cells generated from individuals diagnosed with childhood-onset schizophrenia ...

Scientists reveal how patterns of brain activity direct specific body movements

July 20, 2017
New research by Columbia scientists offers fresh insight into how the brain tells the body to move, from simple behaviors like walking, to trained movements that may take years to master. The discovery in mice advances knowledge ...

Scientists discover combined sensory map for heat, humidity in fly brain

July 20, 2017
Northwestern University neuroscientists now can visualize how fruit flies sense and process humidity and temperature together through a "sensory map" within their brains, according to new research.

Team traces masculinization in mice to estrogen receptor in inhibitory neurons

July 20, 2017
Researchers at Cold Spring Harbor Laboratory (CSHL) have opened a black box in the brain whose contents explain one of the remarkable yet mysterious facts of life.

Speech language therapy delivered through the Internet leads to similar improvements as in-person treatment

July 20, 2017
Telerehabilitation helps healthcare professionals reach more patients in need, but some worry it doesn't offer the same quality of care as in-person treatment. This isn't the case, according to recent research by Baycrest.

1 comment

Adjust slider to filter visible comments by rank

Display comments: newest first

beleg
5 / 5 (1) Aug 28, 2013
First, kudos.
Suppressing the amount of brain specific molecular estrogen causes progressive hearing loss.
The process of storage (memory) and processing of auditory stimuli is suppressed.
A specific molecular progressive deficiency - not a specific molecular defect as for memory loss - is the cause.

Both are reversible.

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.