Alzheimer's disease (AD) is a degenerative brain disorder characterized 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 double in incidence in 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 in the brain parenchyma or in blood vessel walls. Abeta amyloid formation, deposition and persistence in brain is believed to play a central role in AD pathogenesis by contributing to neuronal loss and memory dysfunction, and therefore has become a central target for the development of new drugs for the treatment of AD and related disorders. In AD, there is currently no cure or substantially effective treatment, and the patient usually dies within 3-10 years from disease onset. Our previous studies has led to the identification of a natural substance derived from the amazon rain forest woody vine, Uncaria tomentosa (i.e. Cat's claw), referred to as PTI-00703, which acts a potent inhibitor of Abeta fibril formation/growth, and causes disruption/disassembly of pre-formed Abeta fibrils. In Phase I of our studies, we used assay guided fractionation and HPLC to isolate, test and characterize active ingredients within PTI-00703 that possess potent AB fibrillogenesis inhibitory activity. A number of major ingredients (collectively known as PTI-777) were purified and tested in relevant in vitro and animal model assays, and found to possess extremely potent Abeta fibrillogenesis inhibitory activity. In Phase II proposed studies, we will complete structural identification of each of the PTI-777 active components, and pre-clinical studies including in vitro and in vivo blood-brain-barrier penetration studies, use of relevant rat and plaque- producing transgenic mouse models to determine potential inhibitory effects on prevention and clearance of brain amyloid plaques, behavioral studies in rodents, and safety/toxicology, and biodistribution studies for the ultimate identification of a clinical drug candidate. These studies are anticipated to lead to the identification of a new drug candidate for the treatment of Abeta amyloidosis in AD and related disorders which involves use of a naturally-derived compound. Knowledge gained from these studies will also identify structural parameters necessary for the design of new anti-amyloid therapeutics for the treatment of AD and other amyloidoses. PROPOSED COMMERCIAL APPLICATIONS: Alzheimer's disease (AD) currently affects 4-5 million Americans, at an estimated cost of $80-$100 billion. Currently, there is no cure or substantially effective treatment, and the patient usually dies within 3- 10 years from disease onset. Identification of a natural plant-derived inhibitor of Abeta amyloid fibrillogenesis is anticipated to lead to the development of a new drug(s) for the treatment of AD and related disorders.