FUNDING PERIOD: APRIL 1, 2000 - MARCH 31, 2001

Hui Zheng, Ph.D.
Baylor College of Medicine
Houston, TX
Project: Role of Presenilin-1 in Beta-Catenin Interaction In Vivo.

The PS1 gene is expressed throughout the bodies of all mammals. The complete loss of the PS1 gene in laboratory mice causes a lethal condition in mouse embryos. However, specialized mouse strains that have been engineered to express the human PS1 in the central nervous system, but not elsewhere, can survive. Dr. Zheng has found that these mice develop epidermal hyperplasia and neoplasm, or skin cancer, and that the skin cancer phenotype is similar to that found for transgenic mice that exhibit overactivity in the molecule Beta-Catenin. Dr. Zheng has proposed that this molecule interacts with PS1 and plays a role in cell signaling. In this study, she is attempting to determine the molecular mechanisms of PS1 in the growth of tumors. Then the discovery will be utilized to generate specific mutations in PS1 to further examine its interaction with Beta-Catenin. Because this technique allows the survival of mice whose expression of PS1 has been inhibited, it is hoped that a better understanding of the role of PS-1 in adult tissues will be attained.

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FUNDING PERIOD: APRIL 1, 1999 - MARCH 31, 2001

Gabrielle L. Boulianne, Ph.D.
The Hospital for Sick Children
Toronto, Ontario, Canada
Project: Genetic Modifiers of Presenilin

This project is aimed at the identification of genes that may modify the susceptibility to, or severity of, Alzheimer's disease. The model organism Drosophila (the fruit fly) is being used to perform a screen for genes that interact genetically with the Drosophila presenilin gene. Dr. Boulianne is also screening for proteins that physically interact directly with presenilin. Candidate genes identified through these approaches will be evaluated in transgenic mice for their ability to contribute to the development of an Alzheimer's disease phenotype. The results of this study could further the goal of creating a more useful animal model for the discovery of additional Alzheimer's-related genes.

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Ian Ashley Bush, M.D., Ph.D.
Harvard Medical School, Massachusetts General Hospital
Boston, MA
Project: Oxidation and Zinc in Alzheimer's disease

Metal ions play important roles in many biological processes and high concentrations of copper, zinc, and iron are found in the beta-amyloid (Ab) plaques characteristic of Alzheimer's disease. Dr. Bush has hypothesized that these metal ions may help hold the Ab subunits together as insoluble aggregates. In addition, Dr. Bush and his colleagues have also recently found that copper and iron ions cause the production of harmful hydrogen peroxide and reactive oxygen species from the Ab subunits, and this may contribute to neurotoxicity. The research team is now using a transgenic mouse model to examine whether zinc may be involved in hydrogen peroxide production and if zinc is abnormally distributed in the amyloid precursor protein (APP). Using the same model, he will determine if the Ab deposits are assembled by zinc and whether they can be resolubilized by zinc chelators.

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Steven Estus, Ph.D.
University of Kentucky
Lexington, KY
Project: tPA and Plasmin Modulate Beta-Amyloid

Dr. Estus is focusing on the clearance of beta-amyloid (Ab) by a protease, or an enzyme that digests proteins, called plasmin. Plasmin is normally converted from an inactive form, called plasminogen, to the active form by a protease called tissue plasminogen activator (tPA). Dr. Estus has found that Ab can increase the production of tPA in neuronal cells in culture and that Ab can activate tPA to digest plasminogen into the active plasmin. Plasmin can in turn digest Ab into small fragments. On the basis of these observations, Dr. Estus has hypothesized that Ab causes the increased plasmin activity, which then degrades Ab by proteolysis, and that plasmin serves a protective function by clearing Ab from the brain. In addition, an inhibitor of plasmin production, called plasminogen activator inhibitor (PAI-1), is increased during the inflammation that occurs in Alzheimer's disease. Dr. Estus proposes a "feed forward" model in which inflammation during Alzheimer's disease causes PAI-1 production, which inhibits plasmin. Plasmin inhibition results in more Ab production, damage, and inflammation, perpetuating the cycle. To evaluate this model, Dr. Estus will determine if the results observed in vitro occur in a living system by using genetically engineered mice that either over-produce tPA or are deficient in tPA. This study was partially funded through the Irwin Lee Challenge Grant.

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Alison Goate, D.Phil.
Washington University School of Medicine
St. Louis, MO
Project: Notch Signaling as a Model to Determine the Function of PS1

Mutations in the gene presenilin 1 (PS1) can cause Alzheimer's disease and result in increased levels of Ab42, a form of APP that causes amyloid plaques. Other data have suggested that PS1 is required for normal APP processing, but the precise function of PS1 in APP processing is unknown. PS1 also appears to be necessary for signaling through the Notch pathway. The Notch pathway begins on the surface of cells, and turning it on is important during embryonic development. The interaction of Notch with PS1 is easier to study than the interaction of PS1 with APP, and Dr. Goate is taking advantage of this fact to better understand the function of PS1. Using the information gained from studying PS1-Notch interactions, she will then be able to ask more informed questions about PS1-APP interactions, and how these interactions are altered in Alzheimer's disease.

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Steven L. Gonias, M.D., Ph.D.
University of Virginia
Charlottesville, VA
Project: ß-Amyloid Peptide/a2-Macroglobulin Interactions

It has been suggested that the protein a2-macroglobulin (a2M) could be an inhibitor of beta-amyloid (Ab) aggregation. The goal of this study is to elucidate the nature of the interaction between a2M and the Ab peptide. Dr. Gonias will accomplish this by first identifying the site in a2M which binds to Ab. Because a2M also has important interactions with various growth factors and cytokines that have been implicated in Alzheimer's disease, Dr. Gonias will also attempt to determine if a2M-Ab interaction alters a2M binding to cytokines. One possible outcome of these studies is the identification of novel peptides that have the ability to alter Ab fibril formation -- an activity with potential therapeutic value for Alzheimer's disease.

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Mary F. Knauer, B.Sc., Ph.D.
University of California
Irvine, CA
Project: Domain Analysis of PN2/APP751 - Interactions with LRP

Dr. Knauer is studying the interaction of two forms of the amyloid precursor protein (also known as Protease nexin 2 or PN2) with the low-density lipoprotein receptor related protein (LRP). By binding to LRP, PN2 can be reintroduced to the interior of the cell, and there is evidence to suggest that this may be important in Alzheimer's disease. To understand how these proteins interact, the site of binding in the PN2 molecules will be mapped as well as the corresponding binding site in the LRP molecule. This information may be useful for developing molecular mimics, or agonists, that could prevent LRP-PN2 interaction, re-internalization, and, it is hoped, the formation of amyloid beta protein.

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Ka Yee C. Lee, Ph.D.
University of Chicago
Chicago, IL
Project: Interactions of Alzheimer's Beta-Amyloid with Lipid Membranes

Increasing evidence has suggested that the fibril form of Alzheimer's beta-Amyloid (Ab) is neurotoxic in Alzheimer's disease, and in vitro evidence has suggested that Ab fibrils can be formed at very low peptide concentrations if membrane lipids are present. Dr. Lee's long-range goal is to understand the role of membrane lipids in Ab neurotoxicity. She is screening Ab peptides (Ab-140 and Ab-142) for specific interactions with a variety of individual membrane lipids and with lipid mixtures. After the initial screening, she will use a combination of optical and physical techniques to further characterize the association of Ab peptides with lipids and the effects of the peptides on lipid membranes. She will also characterize fibril formation and obtain high resolution images with atomic force microscopy. Dr. Lee's investigation is one of two studies funded by the Irwin Lee Challenge Grant.

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Stanley B. Prusiner, M.D.
University of California
San Francisco, CA
Project: Synthetic Peptides Transmitting Prion Disease in Mice

This project is a further development of Dr. Prusiner's previously begun study, Inducible Prion Diseases Caused by Artificial Mutations (see below). He is now attempting to transmit prion disease in mice using synthetically processed prions. Synthetic peptides are being used to help filter out variables in nature other than the prion that could cause prion disease. To complete this study, Dr. Prusiner received the American Health Assistance Foundation's 25th Anniversary Research Award.

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Inez Vincent, Ph.D.
University of Washington
Seattle, Washington
Project: Mitotic cdc2 Kinase and Alzheimer's Neurodegeneration

Dr. Vincent is exploring the hypothesis that some of the processes that cause cancer in dividing cells can also occur in non-dividing neurons. Because neurons cannot divide, these processes may lead to cell degeneration and cell death. She has already found that some of the proteins that are key to cell division and cell growth are present in the dying neurons of Alzheimer's disease. These cell proteins are sometimes detectable in neurons even before the appearance of the lesions characteristic of AD. In this study, Dr. Vincent is testing whether introducing these cell cycle proteins into normal neurons will produce AD lesions. Once this question is answered, she will then attempt to determine if the known genetic mutations associated with AD affect the expression of the cell cycle proteins, and if so, how they do so.

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Huaxi Xu, Ph.D.
The Rockefeller University
New York, NY
Project: Estrogen and Presenilin 1 in APP Trafficking and Aß Generation

Postmenopausal women who take estrogen as part of a long-term program of estrogen replacement are less likely to get Alzheimer's disease, or more likely to get it at an older age. Dr. Xu and coworkers were the first to show that estrogen may actually prevent or delay Alzheimer's by slowing the secretion of amyloid from neurons. Dr. Xu is working toward an understanding of how estrogen inhibits the production of toxic amyloid. By using techniques similar to the proposed studies on estrogen, Dr. Xu is also studying how presenilin affects the precursor protein, from which amyloid is derived. It is hoped that a better understanding of the mechanism behind amyloid secretion will lead to interventions to prevent, slow, or reverse the disease.

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