(from parent application) Despite significant progress in Alzheimer?s disease (AD) in general and tau pathobiology in particular, there is still no effective treatment or prevention for AD or any other tauopathy. To develop such therapy, detailed knowledge of the structural biology and structure?activity relationship of tau is needed, including the way sequence alterations and post-translational modifications affect tau self-assembly into toxic oligomers and aggregates, and how these parameters impact tau seeding and toxicity. Here, we propose a systematic, detailed study of these aspects of tau pathology taking advantage of recent developments in mass-spectrometric, biochemical, and cell biology methods. We will study the effect of primary-structure alterations and post- translational modifications on tau oligomerization and aggregation in vitro and compare recombinant and in-vivo generated tau. We will then examine how all of these factors affect tau seeding using a recently developed highly sensitive biosensor cell line. To advance therapy development, we will also test the effect of assembly modulators on tau self-assembly and seeding. A unique aspect of the project is the combination of expertise of the PI and Co-I groups, which will allow obtaining insight into the structure?activity relationship of tau on multiple levels and answering currently pending questions about the complex processes governing this crucial aspect of AD.

Public Health Relevance

This project addresses the essence of ?Capturing Complexity in the Molecular and Cellular Mechanisms Involved in the Etiology of Alzheimer's Disease? Announcement by NIH. This is a particularly pressing goal in view of the rapid aging of the American population and the fast increasing costs of care for patients with Alzheimer?s disease. We address this call by a systematic study of structural variations and molecular modulators of the protein tau, one of the main proteins responsible for the destruction of brain cells in Alzheimer?s disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Multi-Year Funded Research Project Grant (RF1)
Project #
3RF1AG054000-01A1S1
Application #
10241797
Study Section
Program Officer
Yang, Austin Jyan-Yu
Project Start
2017-07-15
Project End
2022-03-31
Budget Start
2020-12-15
Budget End
2022-03-31
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Neurology
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095