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2014 Grants - Lu
Validation of cis-Tau as a Therapeutic Target for Alzheimer’s Disease
Kun Ping Lu, M.D., Ph.D.
Beth Israel Deaconess Medical Center
2014 Investigator-Initiated Research Grant: Discovery-Validation of Therapeutic Targets for Developing Novel Interventions for Alzheimer’s Disease
Tau is a protein thought to play an important role in the molecular mechanisms of Alzheimer’s disease and related conditions. Normally, tau functions as part of the cell structure, but in Alzheimer’s disease it becomes abnormally modified by the addition of chemical phosphate groups through a process called phosphorylation. Excessive phosphorylation of tau leads to the disruption of important cellular structures and formation of neurofibrillary tangles, one of the characteristic features of Alzheimer’s disease in the brain.
Kun Ping Lu, M.D., Ph.D., and colleagues have been studying the phosphorylation of tau and how it leads to tangle formation in nerve cells. The attachment of phosphate to tau can occur in two different orientations, known as ‘cis’ and ‘trans.’ Dr. Lu’s team found that cis-orientation of phosphate on tau is associated with tangle formation, but trans-orientation of phosphate on tau is not.
Dr. Lu and colleagues have recently developed an antibody that binds to cis-phosphorylated tau but not trans-phosphorylated tau. Furthermore, this antibody also directs the immune system to remove cis-phosphorylated tau from the brain. They have proposed a series of experiments to further characterize how the antibody may prevent the formation of neurofibrillary tangles in the brain.
For these studies, the researchers will use mice genetically altered to be susceptible to the development of neurofibrillary tangles in the brain. They will test whether antibodies to cis-phosphorylated tau are able to prevent the initiation and accumulation of tau tangles. They will also test whether such treatments can slow or prevent declines in brain function in these animals. These studies could lead to tests of such antibodies in humans with early-stage Alzheimer’s disease.