2010 New Investigator Research Grant (NIRG)

Tau-Mediated Axonal Transport Dysfunction

Nicholas M. Kanaan, Ph.D.
Michigan State University
East Lansing, MI - United States

Tau protein normally helps maintain the structure of brain cells. But in Alzheimer's disease, the modification of tau through phosphorylation (or the adding of phosphate molecules) becomes abnormal. Abnormally phosphorylated tau has been shown to play a significant role in Alzheimer's disease, often in the disorder's earliest stages. These mutant tau forms typically accumulate into tangles and other harmful clumps, and the aggregates tend to damage nerve cells. Scientists, however, are unclear exactly how mutant tau exerts its toxicity.

Current research has focused on how tau may affect the function of axons. Axons are armlike cellular structures that help transport nutrients and other compounds around the cell. But these structures become damaged in Alzheimer's disease, and their ability to transport compounds becomes hindered. In preliminary studies with squid axons, Nicholas M. Kanaan, Ph.D., and colleagues found that axonal transport of compounds becomes inhibited in a process involving the phosphatase-activating domain (PAD), a region at the end of a tau molecule. This process also leads to the phosphorylation of tau.

For their proposed grant, Dr. Kanaan and colleagues will use cultured neurons to test the hypothesis that PAD hinders axonal transport through a process that phosphorylates tau. The researchers also hope to confirm the precise biological mechanisms underlying this process.

Results of this effort could shed new light on the exact roles of abnormal tau in Alzheimer's disease. They could also lead to targeted, tau-based therapies for the disorder.