The study by a team of Columbia University Medical Center (CUMC) researchers, 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 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 dentate gyrus (DG) of eight people, ages 33 to 88, all of whom were free of brain disease. The team also analyzed cells from their entorhinal cortex (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.
"The first question was whether RbAp48 is downregulated in aged mice, and indeed, that turned out to be the case-there was a reduction of RbAp48 protein in the DG, lead author Elias Pavlopoulos, PhD, associate research scientist in neuroscience at CUMC said.
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.
In another experiment, the researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice.
Eric R. Kandel said that their study showed that this protein 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.
The study is published in the journal of Science Translational Medicine.
--ANI (Posted on 29-08-2013)