Scientists say they have discovered a protein deficiency in the brain that is a major cause of age-related memory loss, according to a study published online in the journal Science Translational Medicine.
The researchers, from Columbia University Medical Center (CUMC), say this discovery offers the "strongest causal evidence" that age-related memory loss and Alzheimer's disease are individual recognizable conditions.
The study, conducted on postmortem human brain cells and in mice, revealed that the hippocampus in the brain - a region that plays an important part in memory, lacks a protein called RbAp48 in those who experience age-related memory loss.
The finding suggests that a deficiency of this protein is a cause of memory loss, but more importantly, the researchers say this form of memory loss is reversible.
They began conducting this current study in order to seek direct evidence that Alzheimer's disease is a completely separate condition from age-related memory loss.
Previous research has suggested that Alzheimer's disease hinders a person's memory by affecting the entorhinal cortex (EC) in the brain. The EC is a region that provides important pathways to the hippocampus.
According to the study authors, it was thought that age-related memory loss was an early sign of Alzheimer's, but they add that recent evidence suggests age-related memory loss is a separate process that affects the dentate gyrus (DG). This is a subregion in the hippocampus that has direct input from the EC.
Researchers have discovered that the RbAp48 gene is a cause of age-related memory loss, setting it apart from Alzheimer's disease.
RbAp48 gene discovered
For the study, the researchers conducted microarray (gene expression) analyses of postmortem brain cells from the dentate gyrus of eight people aged 33 to 88, who were all free of brain disease.
As a control, they also analyzed brain cells from the entorhinal cortex, given that the EC brain structure is unaffected by aging, the researchers say.
From this, 17 candidate genes were found that could be linked to aging in the DG. The gene RbAp48 showed the most significant changes, with its expression deteriorating as the study subjects aged.
The next step involved genetically inhibiting the RbAp48 gene in the brains of healthy young mice. The mice demonstrated the same form of memory loss when tested by object recognition and water maze memory tests. However, their memory returned to normal when the RbAp48 gene was switched off.
Functional MRI (fMRI) scans were conducted on the mice who had the RbAp48 gene, which showed a specific effect in the DG, similar to the effect seen in fMRI scans of aged mice, monkeys and humans, the researchers say.
They add that the effect of the gene on the DG also showed defects in molecular mechanisms usually found in old mice. Once again, when the RbAp48 gene was switched off, the DG profile shown in the fMRI scans and molecular mechanisms returned to normal.
Dr. Eric Kandel, co-director of Columbia University's Mortimer B. Zuckerman Mid Brain Behavior Institute, says:
"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."
Age-related memory loss 'reversible'
The researchers executed another experiment, using viral gene transfer to increase RbAp48 expression in the DG of the aged mice.
Results from memory tests revealed that this improved the memory of the mice, and they even showed results that were comparable to the young mice.
Dr. Kandel says the fact they have been able to reverse age-related memory loss in the mice is very encouraging.
"Of course, it's possible that other changes in the DG contribute to this form of memory loss," he adds.
"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."
Potential targets for therapeutic interventions
The researchers say that the findings of this study suggest that the RbAp48 protein works through a pathway in the brain called PKA-CREB1-CBP. From earlier studies, this pathway was found to be important for age-related memory loss in the mice.
The study authors say that if this pathway can be "enhanced" alongside the RbAp48 protein, these could be targets for "therapeutic interventions."
"Whether these compounds will work in humans is not known. But the broader point is that to develop effective interventions, you first have to find the right target," says Dr. Scott Small, director of the Alzheimer's Research Center at CUMC.
"Now we have a good target, and with the mouse we have developed, we have a way to screen therapies that might be effective, be they pharmaceuticals, nutraceuticals, or physical and cognitive exercises."
Dr. Small adds that there has been a lot of "handwringing" over the failures of drugs trials based on findings from mouse models of Alzheimer's. But he says this study is different:
"Alzheimer's does not occur naturally in the mouse. Here, we have caused age-related memory loss in the mouse, and we have shown it to be relevant to human aging."