Research ArticleNeuroscience

Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48

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Science Translational Medicine  28 Aug 2013:
Vol. 5, Issue 200, pp. 200ra115
DOI: 10.1126/scitranslmed.3006373

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We do not know why, but we think we know where: Age-related memory loss begins in the dentate gyrus of the brain. (Alzheimer’s disease starts in nearby entorhinal cortex and other parts of the hippocampus.) To understand better why we forget more easily as we age, Pavlopoulos et al. gained access to eight human brains and looked carefully for proteins that rose and fell in the dentate gyrus with age. One was particularly notable, RbAp48, a histone-binding protein that regulates transcription and decreases in expression in older people. Exploring its function in mice led the authors to conclude that RbAp48 participates in the dentate gyrus dysfunction that becomes more prominent with aging and could potentially be a target for treatment of age-related memory decline.

By first searching for proteins that are modulated in an age-related fashion in the human brain, the authors firmly rooted their investigation in the translational space. Their subsequent experiments in mice were designed to examine the protein’s function in ways that would have been impossible in humans. Key to validating RbAp48’s function was a transgenic mouse line that carried a dominant-negative inhibitor of RbAp48, but only in the forebrain. The authors could manipulate expression of RbAp48 at will by switching it on and off with artificial triggers. Prematurely inhibiting RbAp48 in young mice resulted in memory deficits just like those seen naturally in older mice. Increasing RbAp48 in older, more forgetful mice restored their memory to its youthful vigor. And not only behavior was affected. Functional magnetic resonance imaging showed that the dentate gyrus in the artificially impaired young mice did not work properly, and molecular assays showed abnormal histone acetylation.

Further exploiting their transgenic mice, the authors also support the idea that RbAp48 acts through the protein kinase A (PKA)–cyclic adenosine monophosphate (cAMP) response element–binding protein 1 (CREB1)–CREB-binding protein (CBP), a well-understood signaling pathway. Agents that enhance signaling through PKA and CREB (cAMP signaling) are already known to improve age-related problems in hippocampal function in mice, so it is a logical next step to test these drugs for therapeutic use in treating age-related memory problems in people.

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