Identification of Proteins That Reduce Pathological Aggregates in the Brain

About the Research Project
Program
Award Type
Standard
Award Amount
$300,000
Active Dates
July 01, 2021 - June 30, 2024
Grant ID
A2021038S
Goals
The goal of this project is to determine which proteins associate with tau aggregates and identify modifiers that reduce these pathological inclusions.In Specific Aim 1, we will identify tau-associated proteins and study their role in aggregate formation in cell culture models in vitro. In Specific Aim 2, we will identify tau-associated proteins and their role in tau pathology in the context of intact brain tissue models ex vivo. In Specific Aim 3, we will determine the role of novel tau-associated proteins in AD pathogenesis, by validating them in human brain tissue and performing functional studies on the most promising candidates for future therapy development.
Summary
A major hallmark of Alzheimer’s disease (AD) is the formation of pathological aggregates composed of mainly microtubule-associated protein tau. Although these protein aggregates are believed to play a pivotal role in the disease process, there is a relatively poor understanding of the composition and molecular environment of these insoluble aggregates, and how their formation, toxicity, and spread across brain regions is regulated.
The goal of this project is to identify proteins that associate with these aggregates that may be contributing to tau pathology in AD. Studying tau aggregates has been hampered by limitations of classical affinity-purification methods. To overcome this technical hurdle, the laboratory staff has established a novel method to precisely map the composition of insoluble protein aggregates in the context of living brain tissue via proximity labeling and proteomic analysis. The researchers have further optimized this method to study the transition of tau from its physiological to its pathological form in cultured neurons and brain tissue models of AD.
This project will provide novel insights into cellular pathways and molecular mechanisms of neurodegeneration, by identifying different functional classes of tau-associated proteins that play a direct role in the disease process of AD, and further validation in human patient samples as candidate biomarkers and targets for future therapy development.
Unique and Innovative
In this project we are using a unique combination of innovative proximity labeling and proteomics methods with advanced tissue culture models for the discovery of tau-associated modifiers of protein aggregation and toxicity. This novel approach will allow us to overcome limitations of classical affinity-purification methods to identify the composition and proximal molecular environment of insoluble protein aggregates in the context of living brain cells.
Foreseeable Benefits
The aim of this project is to overcome a critical gap in our knowledge of the identity of tau-associated proteins that mediate its aggregation and toxicity. At the end of these studies, we will have gained a better understanding of the tau interactome in AD, we will have identified candidate proteins that play a direct role in the tau-mediated pathophysiology of AD, validated them in human patient samples, and functionally characterized them as candidate biomarkers and potential targets for future therapy.
Grants
Related Grants
Alzheimer's Disease Research
Unlocking Tau’s Secrets: Human Brain Cells in the Mouse Brain
Active Dates
July 01, 2024 - June 30, 2026
Principal Investigator
Wenhui Qu, PhD
Unlocking Tau’s Secrets: Human Brain Cells in the Mouse Brain
Active Dates
July 01, 2024 - June 30, 2026

Principal Investigator
Wenhui Qu, PhD
Alzheimer's Disease Research
Assessing the Impact of Blood Brain Barrier Dysfunction on CSF Tau Levels in Alzheimer’s Disease
Active Dates
July 01, 2024 - June 30, 2026
Principal Investigator
Joshna Gadhavi, PhD
Assessing the Impact of Blood Brain Barrier Dysfunction on CSF Tau Levels in Alzheimer’s Disease
Active Dates
July 01, 2024 - June 30, 2026

Principal Investigator
Joshna Gadhavi, PhD
Alzheimer's Disease Research
Does the Little-Studied Big Tau Protect Against Alzheimer's Disease?
Active Dates
July 01, 2023 - June 30, 2025
Principal Investigator
Daheun Chung, PhD
Does the Little-Studied Big Tau Protect Against Alzheimer's Disease?
Active Dates
July 01, 2023 - June 30, 2025

Principal Investigator
Daheun Chung, PhD