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Jan 15, 2010

Researchers Identify Proteins that Contribute to Memory Loss and Alzheimer Disease

  • A scientific group has identified three kinases that dismantle connections within brain cells, which may lead to memory loss associated with Alzheimer 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.

    “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,” points out Travis Dunckley, Ph.D., an associate investigator in the Translational Genomics Research Institute’s (TGen) neurodegenerative research unit. Dr. Dunckley was also the senior author of the paper, which appears in this month's edition of BMC Genomics and is titled “High-content siRNA screening of the kinome identifies kinases involved in Alzheimer disease-related tau hyperphosphorylation.”

    Tau performs a critical role in the brain by helping bind together microtubules, which are subcellular structures that create scaffolding in the neurons. This allows neurons to stretch out along bridges called axons. Under normal circumstances, kinases regulate tau phosphorylation to enable the microtubules to unbind and then bind again, allowing brain cells to connect and reconnect with other brain cells.

    “This facilitates the ability of people to form new memories, to form new connections between different neurons, and maintain those memories,” Dr. Dunckley explains.

    A signature of Alzheimer disease, though, is tau hyperphosphorylation, where tau creates neurofibrillary tangles. "When tau protein is hyperphosphorylated, the microtubule comes apart, basically destroying that bridge, and the neurons can no longer communicate with each other,” according to Dr. Dunckley.

    The TGen-led team used siRNA to screen all 572 known and theoretical kinases within human cells. They identified 26 associated with the phosphorylation of tau. Of these 26, three of them—EIF2AK2, DYRK1A, and AKAP13—were found to cause this hyperphosphorylation. They also showed that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways.

    The next step will be to identify 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 disease, whereby we could modify the progression of tau pathology,” says Dr. Dunckley. “This was a screen to identify what the relevant targets are. Now we want to match those targets to treatments.”

     



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