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Grants > Identification of Proteins That Reduce Pathological Aggregates in the Brain Updated On: Feb. 2, 2025
Alzheimer's Disease Research Grant

Identification of Proteins That Reduce Pathological Aggregates in the Brain

Tau
a headshot of Dr. Rossoll

Principal Investigator

Wilfried Rossoll, PhD

Mayo Clinic Jacksonville

Jacksonville, FL, USA

About the Research Project

Program

Alzheimer's Disease Research

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.