A team of Columbia University Medical Center (CUMC) researchers reported in Science Translational Medicine that a deficiency of a protein, RbAp48, significantly contributes to age-related memory loss, and that this memory loss differs on a molecular and anatomical level from that thought to be associated with Alzheimer’s disease (AD).

To characterize age-related memory loss and potentially distinguish it from AD, the researchers explored its “molecular underpinning” in the dentate gyrus (DG), a subregion of the brain’s hippocampal formation where memory formation occurs and which is thought to be affected by aging.

In conducting their study, the investigators examined gene expression in human postmortem tissue from young and older individuals in two hippocampal regions, the DG and the entorhinal cortex (EC), a neighboring subregion unaffected by aging, known to be the site of onset of AD, and part of a widespread neural network that participates in memory and navigation.

The investigators identified 17 genes that showed reliable age-related changes in the DG. The most significant change, they reported, was an age related decline in RbAp48, a histone-binding protein that modifies histone acetylation, thereby contributing to the control of gene expression.

The scientists also generated a transgenic mouse that expressed a dominant negative inhibitor of RbAp48 in the adult forebrain. Inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel objective measurements.

Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG of the transgenic animals, which corresponded to a regionally selective decrease in histone acetylation. Up-regulation of RbAp48 in the DG of aged wild-type mice ameliorated age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation.

Together, they concluded, these findings show that the DG is targeted by aging, and point to molecular mechanisms of cognitive aging that could serve as valid targets for therapeutic intervention.

Eric Kandel, M.D., university professor & Kavli Professor of Brain Science, and also co-director of Columbia’s Mortimer B. Zuckerman Mind Brain Behavior Institute, noted that, “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.”

Dr. Kandel was a recipient of the 2000 Nobel Prize in Physiology or Medicine for his research on the physiological basis of memory storage in neurons, sharing the prize with Arvid Carlsson and Paul Greengard.

The study, “Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48,” was published in the August 28 online edition of Science Translational Medicine.

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