Tau cleavage and the formation of oligomers in Alzheimer Disease

ABSTRACT Project Title: Tau cleavage and the formation of oligomers in Alzheimer’s Disease Principal Investigator: FERREIRA, Adriana B. Institution: Northwestern University Background: Alzheimer’s Disease (AD), the most frequent cause of dementia associated with aging, belongs to a host of neurodegenerative diseases called tauopathies. Aside from tau hyperphosphorylation, little is known about the role of other posttranslational modifications of this microtubule-associated protein in tauopathies. Recently, we obtained data indicating that calpain-mediated tau cleavage leading to the generation of a 17 kDa tau fragment is a conserved mechanism underlying neurodegeneration in multiple tauopathies. Furthermore, our studies indicated that the 17 kDa tau fragment has intrinsic toxic effects and is not merely a marker of neuronal degeneration in both central neurons that developed in culture and in AD animal model systems. However, the mechanisms by which this tau fragment could induce neurotoxicity remain poorly understood. Hypothesis: Preliminary evidence obtained recently in my laboratory suggests that 17 kDa tau aggregates are present in the hippocampus and temporal cortex of AD subjects. Based on this information, we hypothesize that the 17 kDa tau fragment could exert its neurotoxic effects, at least in part, by modulating the formation of tau aggregates. Specific Aim: The goal of this project is to assess the aggregation properties of the 17 kDa tau fragment and analyze to what extent 17 kDa tau modulates the aggregation of full-length tau. Design: To assess the 17 kDa tau fragment aggregation properties and its effects on the formation of full-length tau filaments, we will perform in vitro experiments by means of light scattering and electron microscopy analysis. Immunoelectron microscopy will be performed using a specific 17 kDa tau antibody recently obtained and characterized in my laboratory.