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Researchers identify proteins that might contribute to memory loss and Alzheimer's disease
Date:1/15/2010

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.

TGen investigators created sophisticated tests to look at 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 hyperphosphorylation of tau, permanently dismantling the microtubule bridges.

"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.

Dr. Eric Reiman, clinical director of TGen's Neurogenomics Division and executive director of the Banner Alzheimer's Institute, explained that tau holds together the skeleton inside neurons. When phosphate molecules stick to tau proteins, the skeleton falls apart and the neurons begin to retract their synaptic branches and die, leading to memory loss and thinking problems.

In this study, researchers used a molecular tool called siRNA to screen the entire human genome, said Dr. Reiman, a co-author of the scientific paper. This tool enabled the TGen-led team to discover which proteins, when genetically turned off, prevent phosphate molecules from sticking to tau. The three kinases, or proteins, that appear to contribute to the formation of brain tangles, can now be targeted by protein-inhibitor drugs.

"This study used a powerful tool to discover three proteins that may be involved in tangle formation. If safe and well-tolerated tangle-busting medications can be developed, they offer great promise in the treatment of Alz
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Contact: Steve Yozwiak
syozwiak@tgen.org
602-343-8704
The Translational Genomics Research Institute
Source:Eurekalert

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