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2014 Grants - Moussa
Nilotinib Effects on Parkin-Mediated p-Tau Clearance
Charbel Moussa, Ph.D.
2014 New Investigator Research Grant
The protein tau plays an important role in maintaining brain cell structure. Tau is normally regulated and modified by a process called phosphorylation, or the addition of phosphate molecules. But in Alzheimer’s disease, tau becomes excessively phosphorylated (or hyperphosphorylated) and loses its ability to carry out its normal functions. Hyperphosphorylated tau also tends to clump together into structures called neurofibrillary tangles. These tangles, which are a hallmark of Alzheimer’s, may inhibit cell-to-cell communication in the brain and contribute to brain cell death.
Recent studies have found that an active protein called Abelson (Abl) is associated with phosphorylating tau in Alzheimer’s disease. Abl may also inhibit another protein called Parkin responsible for clearing tau out of the brain. In earlier research, Charbel Moussa, Ph.D., and colleagues found that a drug molecule called Nilotinib — which has been shown to block Abl activity — can increase the protein-clearing abilities of Parkin. Based on these findings, the researchers hypothesize that by moderating Abl activity, they can enhance Parkin-mediated clearance of tau in the brain, lessening the tau-related brain changes seen in Alzheimer’s.
For this grant, Dr. Moussa and colleagues will test their hypothesis using mice engineered to develop Alzheimer’s-like brain changes. They will inhibit Abl activity in the mice by engineering some of the animals to lack Abl and by administering other animals with Nilotinib. They will then test whether blocking Abl will: (1) increase the functional activity of Parkin, (2) reduce the levels of hyperphosphorylated tau in the brain, (3) prevent tau-related brain cell death, and (4) prevent declines in memory and other brain functions in their model systems. Results of this work could improve our understanding of the molecular pathways underlying Alzheimer’s and other brain diseases such as Parkinson’s disease. But more importantly, these findings could contribute to the development of novel drug therapies, such as Nilotinib, for a much needed disease-modifying treatment for Alzheimer’s disease.