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Discovery May Help Identify Drug Therapies to Prevent Dementia

2017-01-16
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Dementia, also known as senility, is a broad category of brain diseases that cause a long term and often gradual decrease in the ability to think and remember that is great enough to affect a person’s daily functioning.




Rutgers University scientists have discovered a molecular pathway in the brain that may help provide answers to long-term memory problems in the elderly and aid researchers in identifying drug-based therapies to prevent dementia.


A molecular pathway that runs from the synapse to the nucleus of neuronal cells has been found to influence memory strength. At the start of the pathway, there is a synaptically localized protein, the transcription factor CRTC1 (CREB-regulated transcription coactivator 1). At the end of the pathway, there is the FGF1, or fibroblast growth factor 1, gene, which controls essential brain cell functions and is important for tissue maintenance, repair, and regeneration.


The Rutgers scientists used laboratory mice to look at how information is transmitted from the synapses—the point where neurons connect and communicate with each other—to the nuclei in the hippocampal neuronal cells. Ultimately, the scientists determined that CRTC1 enhances memory by controlling the expression of FGF1.


Details appeared January 10 in the journal Cell Reports, in an article entitled, “CRTC1 Nuclear Translocation Following Learning Modulates Memory Strength via Exchange of Chromatin Remodeling Complexes on the Fgf1 Gene.” The article describes how the Rutgers scientists used two behavioral paradigms, fear conditioning and object location learning, to find that mice that received a longer period of training expressed a higher activity of the CTRC1 protein, had more robust and stronger gene transcription, and exhibited better long-term memory.


“Following associative learning, synaptically localized CRTC1 is translocated to the nucleus and regulates Fgf1b transcription in an activity-dependent manner,” wrote the article’s authors. “After both weak and strong training, the HDAC3-N-CoR corepressor complex leaves the Fgf1b promoter and a complex involving the translocated CRTC1, phosphorylated CREB, and histone acetyltransferase CBP [CREB-binding protein] induces transient transcription.”


Essentially, the scientists found that the CRTC1 protein’s activation of the FGF1 gene was the link between more intense learning and enhanced memory strength.


“Strong training later substitutes KAT5 for CBP, a process that is dependent on CRTC1, but not on CREB phosphorylation,” the authors explained. “This in turn leads to long-lasting Fgf1b transcription and memory enhancement.”


The study’s co-corresponding authors are Gleb Shumyatsky, Ph.D., an associate professor of genetics, and Shusaku Uchida, Ph.D., a former postdoctoral researcher.


“The memory process is very much the same in both human and mouse brains,” said Dr. Shumyatsky “Our group has been unraveling molecular mechanisms that maintain and improve memory, and what our research tells us is that there are different answers to controlling and improving memory.” The current study, for example, suggests that memory strength relies on activity-dependent changes in chromatin and temporal regulation of gene transcription on specific CREB/CRTC1 gene targets.


“There is a potential that this work could help with memory in the human brain,” noted Dr. Shumyatsky. “We found that the longer the CRTC1 stays in the mouse brain, the stronger the memory.


“Memory decline brings much suffering to the affected individuals and their families and leads to staggering social and economic costs. This work may provide scientists with answers and therapeutic help in the future for those going through normal aging or suffering from dementia.”

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