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FROM THE LAB OF A NOBEL LAUREATE: New Molecular and Anatomic Evidence Helps Distinguish Cognitive Aging from Alzheimer’s Disease

Robinson, Richard

doi: 10.1097/01.NT.0000436535.94925.a4
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Looking at gene expression profiles from the dentate gyrus and entorhinal cortex in eight human non-Alzheimer's disease brains, investigators identified 17 genes whose expression in the dentate gyrus was significantly increased or decreased with age. Among these, the one showing the largest change was retinoblastoma associated protein of 48 kilodaltons, or RbAp48.

Normal age-related memory loss has a different anatomic and molecular substrate than Alzheimer's disease (AD), according to a new study. The report, published in the Aug. 28 issue of Science Translational Medicine, strengthens the case that the two forms of memory loss are distinct entities.

“Many of my colleagues are skeptical that they are different,” said lead researcher Eric R. Kandel, PhD, “and this single paper is not necessarily going to move them to the conclusion that it is a certainty, but I think we've probably provided the most interesting and compelling data so far.” Dr. Kandel is professor of brain science and the director of The Kavli Institute for Brain Science at Columbia University in New York.



Previous work, much of it from the laboratory of co-author Scott Small, MD, also of Columbia, has investigated the differential effects of Alzheimer's disease and normal age-related memory loss (or “cognitive aging”) on various parts of the hippocampus, the seat of declarative and spatial memory. That work has shown clearly that early AD primarily affects the entorhinal cortex, while sparing the dentate gyrus. In contrast, high-resolution functional MRI has suggested that the dentate gyrus, and not the entorhinal cortex, is the initial site of dysfunction in cognitive aging.

But while the pathology of AD has been well characterized, neither cell loss nor protein accumulation is seen in cognitive aging, and no specific molecular changes have been associated with it. “We sought to isolate a molecular correlate of the aging human dentate gyrus, and explore whether this molecule mediates age-related memory loss,” Dr. Kandel said.

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Dr. Kandel and colleagues began by comparing gene expression profiles from the dentate gyrus and entorhinal cortex in eight human non-AD brains, ages 33 to 88. He used age-related changes in expression levels in the entorhinal cortex as a baseline for asking about changes in the dentate gyrus, based on the hypothesis that the entorhinal cortex is relatively spared, while the dentate gyrus is the anatomic focus of cognitive aging.

He found 17 genes whose expression in the dentate gyrus was significantly increased or decreased with age. Among these, the one showing the largest change was retinoblastoma associated protein of 48 kilodaltons, or RbAp48. Its expression in the dentate gyrus declined strongly with age, compared with its expression in the entorhinal cortex. The same change was seen in a repeat study of 10 more human brains.

RbAp48 is a transcription regulator that has a role in histone acetylation and chromatin remodeling, Dr. Kandel explained. It is involved in the so-called CREB1 [cyclic adenosine monophosphate (AMP) responsive element] pathway, which Dr. Kandel identified as playing a key role in neuronal plasticity and long-term memory formation. In 2000, he received the Nobel Prize in Physiology or Medicine for this work. “Switching CREB on activates downstream genes, and leads to growth of new synaptic connections. These transcriptional changes require alterations in chromatin structure, and that is achieved by ancillary proteins that work together with CREB,” including RbAp48.

Turning to mice, he found the same selective age-related decline of RbAp48 in the dentate gyrus, compared with the entorhinal cortex. Gene transfer of normal RbAp48 to aged mice improved their ability on both object recognition and spatial memory tests.

Next, he bred transgenic mice that expressed a dominant negative (inactive) form of the gene, restricting its expression to the forebrain and controlling its temporal expression with an antibiotic sensitive promoter. The gene was kept turned off early — while the endogenous version was active — to allow normal development. When it was then turned on, by withholding the antibiotic, it largely prevented endogenous RbAp48 from binding to histones, mimicking the loss of the protein with age. These mice showed reduced object recognition and spatial memory, effects that could be reversed by reintroducing the antibiotic, turning off the transgene. The behavioral changes correlated with dysfunction in regional cerebral blood volume, as determined by fMRI.

Within the dentate gyrus, Dr. Kandel found reduced acetylation of two histone proteins known to be involved in memory processes, while another histone not so involved was unaffected. Despite the fact that the dentate gyrus is the site of prodigious neurogenesis, which is believed to be involved in memory formation, none of the manipulations in these experiments affected creation or development of new neurons.

“Taken together,” he said, “our data demonstrate that RbAp48 plays an important role in hippocampus-related memory processes, and suggest a causal role of RbAp48 in cognitive aging.”

Why does expression of RbAp48 decline with age? “That's a fascinating question we want to look at,” Dr. Kandel said. “That's the number one question.” He will also be exploring the significance of the other genes that turned up in the initial screen, including DNA helicase, mutations which have been linked to premature aging.

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“This is really a hallmark study in the molecular pathology associated with cognitive aging,” commented Ron Davis, PhD, professor and chair of neuroscience at the Scripps Research Institute in Jupiter, FL. He noted it is relatively rare to find a single research study that spans analysis of human tissue and creation of a mouse model, and that incorporates behavioral, anatomic, transgenic, and imaging approaches. “Overall, it is a beautiful study.”

The results are “promising” for identifying a true difference between Alzheimer's memory loss and cognitive aging, he added. “I would be agnostic on whether we have really found a specific way to dissociate the two, but this is among the best I've seen.”

For Mark Mayford, PhD, associate professor of molecular and cellular neuroscience at Scripps Research Institute in La Jolla, CA, “the most striking result” was the restoration of memory capability in aged mice, by focally boosting their levels of RbAp48.

“I have not seen that anywhere else. It drives your focus on to this very limited group of cells, and suggests that maybe this is one of the key focal points” in age-related memory decline. In addition, he said, the entire study “fits very nicely into very basic mechanisms that have been characterized before” in memory storage. A key direction for future research is to determine more about the genetic program that RBAp48 and CREB set into motion. “We don't know much about the genes they are targeting, and those are the ones actually doing the work.”

Whether and how quickly the insights from this study lead to clinical applications remains to be seen. Dr. Davis noted pharmacological enhancement of RbAp48 might be challenging, since drugs to increase function tend to be harder to develop than ones that inhibit function. In addition, he noted, global enhancement may not be beneficial, as was shown to be the case for cyclic AMP enhancement as a memory booster. Raising its activity in the hippocampus was good for spatial and declarative memory, but was bad for working memory in the prefrontal cortex, he said, citing a 1999 paper in the Journal of Neuroscience.





Perhaps more likely is the use of functional imaging to distinguish cognitive aging from AD. According to Dr. Davis, “If the distinction is shown to be robust, then imaging could be contemplated” for that purpose.

Dr. Kandel agreed, concluding: “I think with imaging, one might be able to detect age-related memory loss, and save a lot of grief for people who worry about getting Alzheimer's disease. For the first time, we have a biological marker.”

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•. Pavlopoulos E, Jones S, Kosmidis S, et al. Molecular mechanism for age-related memory loss: The histone-binding protein RbAp48. Sci Transl Med 2013C;5(200):200ra115.
    •. Kandel ER. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol Brain 2012;5:14.
      •. Transcript and video of Dr. Eric R. Kandel's 2000 Nobel Lecture:
        •. Morozov A, Muzzio IA, Kandel ER, et al. Rap1 couples cAMP signaling to a distinct pool of p42/44MAPK regulating excitability, synaptic plasticity, learning, and memory. Neuron 2003;39:309–325.
          •. Taylor JR, Birnbaum S, Ubriani R, et al. Activation of cAMP-dependent protein kinase A in prefrontal cortex impairs working memory performance. J Neurosci 1999; 15;19(18):RC23.
            •. Neurology Today archive on Dr. Eric R. Kandel:
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