An increasingly diverse and compelling set of experimental observations supports the hypothesis that Abeta fibrillization starts a cascade of events which eventually results in AD. Although much is known about the primary structure of Abeta in plaques and about the core secondary structure of Abeta in fibrils, little is understand about the mechanisms by which nascent Abeta folds and assembles into fibrils. Identification and characterization of fibrillogenesis intermediates and determination of the kinetics of Abeta fibrillogenesis is crucial if thoughtful, focused efforts are to be made to develop therapeutic agents affecting the fibrillogenesis process. Informative studies in this area will not only significantly accelerate the pace of drug discovery for AD, but will also advance efforts to understand and treat other amyloidoses. Our long term goal is to test the above hypothesis in a series of three steps: 1) to elucidate in molecular detail the mechanisms in Abeta fibrillogenesis; 2) to develop chemical agents capable of blocking or reversing key steps in the fibrillogenesis pathway in vitro; and 3) to formulate and clinically test the efficacy of the agents developed in vitro. This proposal focuses on long term goal #1. The three specific aims proposed build on a number of exciting recent experimental findings. These include the discovery of a potential new therapeutic target, the amyloid protofibril: development of a powerful paradigm, using quasielastic light scattering spectroscopy, for the quantitative analysis of Abeta fibrillogenesis kinetics; and identification of a novel Abeta folding intermediate, the study of which could provide important information about the earliest stages of Abeta fibrillogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS038328-02S1
Application #
6353734
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Oliver, Eugene J
Project Start
1998-12-10
Project End
2001-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
2
Fiscal Year
2000
Total Cost
$15,392
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
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