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2006 Grant - Zondlo
Conformational Targeting of Tau and Secretase
Neal J. Zondlo, Ph.D.
University of Delaware
2006 New Investigator Research Grant
Two characteristic features of Alzheimer pathology are neurofibrillary tangles and amyloid plaques. Both of these features result from abnormal clumping of proteins or protein fragments that have other important functions.
In the case of neurofibrillary tangles, which occur inside of nerve cells, the clumps are formed by a protein called tau. Under normal conditions, tau binds to structural parts of the nerve cell, helping the cell to maintain its structure and to transport nutrients. During the disease process, tau becomes modified to an unusual degree by a chemical alteration called phosphorylation. Excess phosphorylation of tau causes it to change its properties so that it forms the disordered arrays known as neurofibrillary tangles.
Exactly how the protein tau changes during this process is not known. Phosphorylations at certain locations on the protein are probably more important than phosphorylations at other locations. Neal J. Zondlo, Ph.D., and colleagues plan to use high-resolution imaging methods to characterize which parts of the protein, and which modifications, cause it to act abnormally and form neurofibrillary tangles.
Similarly, they will characterize the structural properties of several proteins that must assemble themselves in a certain way in order to carry out their collective role in the production of beta-amyloid. This protein fragment, a key toxic factor in Alzheimer's, is the main component of amyloid plaques.
By understanding how these proteins assemble themselves, the researchers hope to identify molecules that disrupt the assembly process and subsequently inhibit beta-amyloid production.