Defining Connections between Oxidative Stress and the Disease Protein, Tau.
MentorHugo Bellen, DVM, PhD
I aim to investigate how the disease protein, Tau, becomes dysfunctional and may contribute to Alzheimer's disease progression, focusing on the imbalance of free radicals that cause oxidative stress. Aim 1: Using a novel, humanized Tau fly model, I will investigate differences between Tau isoforms and mutations on this protein's ability to mediate oxidative stress, caused by elevated reactive oxygen species. This work aims to define how Tau may function prior to the occurrence of Tau pathology in AD. Aim 2: As Tau becomes hyperphosphorylated and aggregates in AD, here I will consider if oxidative stress can contribute to the induction of these aggregates in neurons and glia using Tau fly models. This work aims to gain insights into disease mechanisms that contribute to AD progression.
I am using state-of-the-art genetic technologies to create new Drosophila models for Alzheimer's disease, focusing on Tau. These will promote my ability to ask innovative questions in regard to Tau, oxidative stress, and non-cell autonomous disease mechanisms. It is currently not well understood how oxidative stress may impact Tau aggregation or how Tau can mediate oxidative stress prior to aggregation. Thus, my work is likely to shed important insights onto how reactive oxygen species contribute to Alzheimer's disease progression. The novel fly models I am developing will be valuable tools for other investigators. Current research relies on robust overexpression of human Tau in the fly while a new, humanized Tau fly model will allow me and others to use the genetic tool Drosophila to increase understandings as to how this critical protein functions in the brain and its involvement in Alzheimer's disease. This work is aimed to increase our knowledge of how Alzheimer's disease occurs and progresses.