Researchers discover a primary cause of age-related memory loss

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Scientists discover primary cause of age-related memory loss
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Columbia University Medical Center (CUMC) researchers, led by Nobel laureate Eric R. Kandel, MD, have uncovered a major cause of age-related memory loss, according to a new study published in the online edition of Science Translational Medicine.

The research team found that deficiency of a protein in the hippocampus called RbAp48 is a significant contributor to age-related memory loss. They also say that this form of memory loss is reversible.

Conducted on postmortem human brain cells and in mice, the study provides the best evidence to date that age-related memory loss and Alzheimer's disease are two different and 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," explained Dr. Kandel, who received a share of the 2000 Nobel Prize in Physiology or Medicine for his discoveries related to the molecular basis of memory.

The hippocampus is a region of the brain that plays a crucial role in memory. Studies have shown that Alzheimer's disease interferes with memory by initially acting on the entorhinal cortex (EC), an area of the brain that provides the major input pathways to the hippocampus.

It was originally believed that age-related memory loss was an early indicator of Alzheimer's, but a growing body of evidence suggests that memory loss is a distinct process, which affects a different part of the brain – specifically, the dentate gyrus (DG), a subregion of the hippocampus that receives direct input from the entorhinal cortex (EC).

"Until now, however, no one has been able to identify specific molecular defects involved in age-related memory loss in humans," said co-senior author Scott A. Small, MD, the Boris and Rose Katz Professor of Neurology and Director of the Alzheimer's Research Center at CUMC.

The research team involved in this newest study set out to uncover more direct evidence that age-related memory loss was different from Alzheimer's disease, starting with a gene expression analyses of postmortem brain cells from the dentate gyrus (DG) of eight participants without brain disease who were between the ages of 33 and 88. The team also analyzed cells from the participants entorhinal cortex (EC), using the cells as controls because that region of the brain is unaffected by aging.

The analyses identified 17 candidate genes that could be related to aging in the DG, with the most significant changes occurring in a gene called RbAp48, as that gene’s expression declined steadily over time as the participants aged.

The researchers then conducted mice studies in order to figure out if RbAp48 plays an active role in age-related memory loss.

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"The first question was whether RbAp48 is downregulated in aged mice," said lead author 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 the researchers genetically repressed RbAp48 in the brains of healthy young mice, they discovered they suffered the same memory loss as aged mice did, using object recognition and water maze memory tests as measurements. When they turned off the repression of RbAp48, the memory of the mice returned to normal.

Functional MRI (fMRI) studies of the mice with repressed RbAp48 were also conducted by the researchers, which is when they found a selective effect in the DG that was similar to that seen in fMRI studies of aged mice, monkeys, and humans. This effect of RbAp48 repression on the DG also came with defects in molecular mechanisms similar to those found in old mice. The fMRI profile and defects of the mice with the repressed protein returned to normal when the repression was turned off.

The researchers used viral gene transfer and increased RbAp48 expression in the DG of aged mice in another experiment.

"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," added 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."

According to the findings of the study, the RbAp48 protein mediates its effects in part via a pathway known as PKA-CREB1-CBP, which was found to be important for age-related memory loss in mice from earlier studies the team conducted. As the researchers found, RbAp48 and the PKA-CREB1-CBP pathway are valid targets for therapeutic intervention because agents that enhance this pathway have already been shown to improve age-related hippocampal dysfunction in rodents.

But what about humans?

"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," Small added.

"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."

SOURCE: Science Translational Medicine, "Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48,". Sci Transl Med 28 August 2013: Vol. 5, Issue 200, p. 200ra115 Sci. Transl. Med. DOI: 10.1126/scitranslmed.3006373

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