Gene Expression Study Confirms Age-Related Memory Loss Is Distinct from Alzheimer's Disease

Decline in the activity of the gene that codes for the protein RbAp48 (retinoblastoma binding protein 4) in the hippocampus has been linked to age-related memory loss, a condition not related to Alzheimer's disease.

Investigators at the Columbia University Medical Center (New York, NY, USA) were looking for the genomic and molecular basis for age-related memory loss in the dentate gyrus (DG), a subregion of the hippocampal formation thought to be targeted by aging. To this end, they used DNA microarray analysis to evaluate gene expression in human postmortem tissue harvested from both the DG and the entorhinal cortex (EC), a neighboring subregion unaffected by aging and known to be the site of onset of Alzheimer's disease.

Results from this study revealed that 17 genes demonstrated reliable age-related changes in the DG. The most significant change was an age-related decline in RbAp48, a histone-binding protein that modifies histone acetylation.

To test whether the RbAp48 decline could be responsible for age-related memory loss, the investigators turned to mice and found that, consistent with humans, RbAp48 was less abundant in the DG of old than in young mice. The investigators then genetically engineered a line of mice that lacked expression of RbAp48 in the forebrain. Results published in the August 28, 2013, online edition of the journal Science Translational Medicine revealed that inhibition of RbAp48 in young mice caused hippocampus-dependent memory deficits similar to those associated with aging, as measured by novel object recognition and water maze tests. Functional magnetic resonance imaging studies showed that within the hippocampal formation, dysfunction was selectively observed in the DG, and this corresponded to a regionally selective decrease in histone acetylation.

The use of a viral gene transfer technique to increase RbAp48 expression in the DG of aged mice resulted in the reversal of age-related hippocampus-based memory loss and age-related abnormalities in histone acetylation.

“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 senior author Dr. Eric R. Kandel, professor of brain science at Columbia University and a winner of the 2000 Nobel Prize in Physiology or Medicine. “The fact that we were able to reverse age-related memory loss in mice is very encouraging. Of course, it is 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.”

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