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Alzheimer's Disease Research
Completed Award

Dr. Marc Diamond

Marc Diamond, M.D.

Washington University, School of Medicine
St. Louis, MO

Title: Cell-Cell Transfer and Propagation of Tau Aggregates
Non-Technical Title: Determination of how protein aggregates spread between cells

Duration: April 1, 2010 - June 30, 2013
Award Type: Standard
Award Amount: $400,000

Summary:

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.

Details:

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 organisims, 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.

Publications:

Fuentealba RA, Udan M, Bell S, Wegorzewska I, Shao J, Diamond MI, Weihl CC, Baloh RH: "Interaction with polyglutamine aggregates reveals a Q/N rich domain in TDP-43." Journal of Biological Chemistry 2010 Aug 20;285(34):26304-14. PubMed Icon Google Scholar Icon

Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM: "In Vivo Microdialysis Reveals Age-Dependent Decrease of Brain Interstitial Fluid Tau Levels in P301S Human Tau Transgenic Mice." Journal of Neuroscience. 2011 Sep 14;31(37):13110-13117. PubMed Icon Google Scholar Icon

Fuentealba RA, Marasa J, Diamond MI, Piwnica-Worms D, Weihl CC: "An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors." Human Molecular Genetics. 2011 Nov. PubMed Icon Google Scholar Icon

Fuentealba RA, Udan M, Bell S, Wegorzewska I, Shao J, Diamond MI, Weihl CC, Baloh RH: "Interaction with polyglutamine aggregates reveals a Q/N rich domain in TDP-43"
Journal of Biological Chemistry 2010 Aug 20;285(34):26304-14  PubMed Icon Google Scholar Icon

Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow EM, Diamond MI, Lee VM, Holtzman DM: "In Vivo Microdialysis Reveals Age-Dependent Decrease of Brain Interstitial Fluid Tau Levels in P301S Human Tau Transgenic Mice." Journal of Neuroscience. 2011 Sep 14;31(37):13110-13117  PubMed Icon Google Scholar Icon

Fuentealba RA, Marasa J, Diamond MI, Piwnica-Worms D, Weihl CC: "An aggregation sensing reporter identifies leflunomide and teriflunomide as polyglutamine aggregate inhibitors."
Human Molecular Genetics. 2011 Nov PubMed Icon Google Scholar Icon

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.

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