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Grants > Cell-Cell Transfer and Propagation of Tau Aggregates Updated On: Jan. 19, 2025
Alzheimer's Disease Research Grant

Cell-Cell Transfer and Propagation of Tau Aggregates

a headshot of Dr. Diamond

Principal Investigator

Marc Diamond, MD

Washington University, School of Medicine

St. Louis, MO, USA

About the Research Project

Program

Alzheimer's Disease Research

Award Type

Standard

Award Amount

$400,000

Active Dates

April 01, 2010 - June 30, 2013

Grant ID

A2010051

Goals

This work addresses an overarching question of why neurodegeneration spreads inexorably through the brain. The research will address specifically how aggregates of misfolded tau protein move between cells, and whether they serve as a template that directly seeds or otherwise catalyze further aggregation.

Summary

It is increasingly recognized that neurodegenerative diseases such as Alzheimer’s disease do not destroy the brain randomly. Instead there is an orderly and inexorable progression of degeneration that is associated with accumulation of misfolded proteins, such as the tau protein, in “fibrillar”, or fiber-like, aggregates. Emerging work in the field suggests that this “propagation” of misfolded protein might actually be due to protein aggregates that can jump from cell to cell, spreading the disease through the brain like falling dominoes. This study will help understand how the spread of protein misfolding might occur. If successful, this work will suggest entirely new strategies to treat this problem that are based on blocking the movement of protein aggregates between cells. These strategies would not only apply to Alzheimer’s disease, but would likely apply to multiple diseases such as Parkinson’s disease and ALS (also known as “Lou Gehrig’s Disease”). We are approaching this problem using a cell culture system that we have established over the last five years. It enables us to monitor cell to cell movement of protein aggregates, and to study how this occurs. Additionally we will use animal models to test whether the movement and propagation of aggregates occurs in living organisms, and whether the same basic mechanisms apply that are observed in cells. This proposal is unique because it is testing a cutting-edge idea about the initial development of Alzheimer disease: that progression of disease is due to physical transfer of protein aggregates between cells. This is a completely new approach to the disease, and, if successful, will inspire equally novel therapeutic approaches.

Progress Updates

Neurodegenerative diseases such as Alzheimer’s disease (AD) are known to spread from one part of the brain to another. The mechanism for this spread is unknown, but work from Dr. Diamond’s laboratory and others has suggested that it may be caused by the movement of protein aggregates (clumps) between cells. This grant seeks to understand exactly how the protein aggregates can transfer from cell to cell, and to determine whether this transfer process can trigger further protein aggregation. Dr. Diamond and colleagues have made a lot of progress in the past two years. First, they established cell models to determine when protein from one cell has moved to another, and whether it has triggered further protein aggregation in the second cell. Second, they uncovered how the protein aggregate contacts the outside of the cell and gains entry. Third, they identified antibodies that can block the spread of protein aggregation between cells. This work could provide therapies of AD by finding out how protein aggregates move and spread, and by identifying antibodies and small molecules that can block their movement between cells. Dr. Diamond has filed patents on new diagnostic methods for AD, and with his collaborator, Dr. David Holtzman, has also filed patents on antibodies that may serve as new therapeutics. Thus, this work has substantially advanced the development of new diagnostic and therapeutics for AD.