Age-related Memory Loss Reversed In Mice
August 29, 2013

Age-Related Memory Loss Is A Separate Syndrome Than Alzheimer’s Disease

[ Watch the Video: New Discovery Could Lead to New Treatment for Memory Loss ]

April Flowers for - Your Universe Online

The deficiency of a protein called RbAp48 in the hippocampus has been identified by a team of Columbia University (CUMC) researchers as a significant contributor to age-related memory loss. The team, led by Nobel laureate Eric R. Kandel, MD, also found this type of memory loss is reversible.

The study, published in Science Translational Medicine, was conducted in postmortem human brain cells and in mice. The findings offer the strongest causal evidence that age-related memory loss and Alzheimer’s disease are distinct conditions.

"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. Kandel is also 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. For his discoveries related to the molecular basis of memory, Dr. Kandel received a share of the 2000 Nobel Prize in Physiology or Medicine.

Scientists have found the hippocampus - a brain region that consists of several interconnected subregions, each with a distinct neuron population, plays a vital role in memory. Previous studies have shown that Alzheimer’s disease acts first on the entorhinal cortex (EC) – a brain region that provides the major input pathways to the hippocampus – to hamper memory. Scientists first thought age-related memory loss is an early manifestation of Alzheimer's, but mounting evidence suggests 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 Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and Director of the Alzheimer's Research Center at CUMC.

Dr. Kandel and his team designed the current study to look for more direct evidence that age-related memory loss differs from Alzheimer’s disease. First, the team performed  microarray (gene expression) analyses of postmortem brain cells from the DG of eight people, ages 33 to 88. All of the brains were free of any brain disease. They also analyzed cells from the EC of each brain. The EC serves as a control since that structure is unaffected by aging. The findings identified 17 possible candidate genes that might be related to aging in the DG, with the most significant changes occurred in a gene called RbAp48, whose expression declined steadily with aging across the study subjects.

The research team turned to mouse studies to determine whether RbAp48 plays an active role in age-related memory loss. "The first question was whether RbAp48 is downregulated in aged mice," said 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 RbAp48 was inhibited in the brains of healthy young mice, the research team found the same memory loss as in aged mice. The team used novel object recognition and water maze memory tests to measure the memory loss. When the inhibition of RbAp48 was removed, the mice’s memory returned to normal.

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

In a related experiment, the team use viral gene transfer to increase 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."

The findings suggest RbAp48 protein mediates its effects, at least in part, through the PKA-CREB1-CBP pathway, which had proven in earlier studies to be important for age-related memory loss in the mouse. The researchers say RbAp48 and the PKA-CREB1-CBP pathway are valid targets for therapeutic intervention. Age-related hippocampal dysfunction in rodents has been shown to improve with agents that enhance this pathway.

"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."

Image 2 (below): 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. Image credit: Elias Pavlopoulos, PhD/Columbia University Medical Center