Alzheimer's disease (AD) is a degenerative brain disorder characterize clinically by progressive loss of memory, cognition, reasoning, judgement and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is the leading cause of dementia in the elderly, today affecting 4-5 million Americans, which is expected to increase to 8-10 million Americans within the next 25 years. AD is characterized by the brain accumulation of insoluble fibrillar amyloid deposits containing the beta-amyloid protein (Abeta), either as extracellular amyloid plaques or in blood vessel walls in the brain parenchyma. Abeta amyloid persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction. A variety of other human diseases also demonstrate amyloid deposition and usually involve systemic organs, with the amyloid accumulation leading to organ dysfunction or failure. In AD and """"""""systemic"""""""" amyloid diseases, there is currently no cure or effective treatment, and the patients usually dies within 3-10 years from disease onset. We have identified an orally taken, commercially available dietary supplement which is a plant material (referred to as PTI-00703), and which acts as a potent inhibitor of AD and type II diabetes amyloid fibril formation/growth. The major objective of this Phase I proposal is to isolate and identify the key amyloid inhibitory ingredients within the plant material. Isolated components will be tested in relevant in vitro assays, and the most potent amyloid inhibitors will be purified in sufficent quantities for structural analysis. Extracts of PTI-00703 and the most """"""""active"""""""" amyloid inhibitory ingredients identified by in vitro testing will also be utilized in a rodent model to determine their effectiveness on dissolution/clearance of pre-deposited fibrillar Abeta amyloid in brain. These studies are anticipated to lead to new possible treatments for AD and other amyloid disorders using extracts from a specific natural herbal supplement. Determination of the chemical structure of the """"""""active"""""""" amyloid inhibitory ingredients within the extracted plant material are anticipate to also lead to new drug design for anti-amyloid therapeutics for the future.
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