One Step Closer To Unraveling The Tangle of Alzheimer’s
January 19, 2010
Findings from a multi-year study led by the Translational Genomics Research Institute (TGen) have identified three kinases, or proteins, that dismantle connections within brain cells, which may lead to memory loss associated with Alzheimer's disease. The three kinases were found to cause a malfunction in tau, a protein critical to the formation of the microtubule bridges within brain cells, or neurons. These bridges support the synaptic connections that, like computer circuits, allow neurons to communicate with each other. "The ultimate result of tau dysfunction is that neurons lose their connections to other neurons, and when neurons are no longer communicating, that has profound effects on cognition—the ability to think and reason,'' said Dr. Travis Dunckley, an Associate Investigator in TGen's Neurodegenerative Research Unit and senior author of the scientific paper on the study, published in current edition of BMC Genomics. Under normal circumstances, kinases regulate tau by adding phosphates. This process, called tau phosphorylation, enables the microtubules to unbind and then bind again, allowing brain cells to connect and reconnect with other brain cells. "That facilitates synaptic plasticity. It facilitates the ability of people to form new memories—to form new connections between different neurons—and maintain those memories. So, it's an essential function,'' Dr. Dunckley said. However, sometimes the tau protein becomes hyperphosphorylated, a condition in which the tau creates neurofibrillary tangles, one of the signature indicators of Alzheimer's. "When tau protein is hyperphosphorylated, the microtubule comes apart—basically destroying that bridge—and the neurons can no longer communicate with each other,'' Dr. Dunckley said. This leads to memory loss and thinking problems. "This paper shows, for the first time, these three kinases affect Alzheimer's disease-relevant tau hyperphosphorylation, in which most of the tau protein is now driven into a permanently phosphorylated form,'' Dr. Dunckley said. The next step will be to identify protein-inhibitor drug compounds that can negate the effects of the three kinases linked to tau hyperphosphorylation. "The reason that we did this study was to identify therapeutic targets for Alzheimer's disease, whereby we could modify the progression of tau pathology,'' Dr. Dunckley said. "This was a screen to identify what the relevant targets are. Now we want to match those targets to treatments.''
Jan's Story by Barry Petersen, the multiple Emmy-award winning CBS News correspondent, is the heart-wrenching account of his wife Jan's Early Onset Alzheimer's Disease. Read more.
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