Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment 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 (AB), either as extracellular amyloid plaques in the brain parenchyma or in blood vessel walls. AB 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. . Our Phase I SBIR studies have identified the critical importance of highly sulfated glycosaminoglycans and related macromolecules for the in vitro induction of maltese-cross congophilic amyloid plaque-like deposits, which are morphologically and ultrastructurally strikingly similar to those amyloid plaques derived from AD brain. Using this technology, we have begun to develop in vitro screening technologies and a new non-trangenic rodent model of amyloid plaque deposition and persistence, which is being used to rapidly identify potential anti-amyloid plaque therapeutics that target amyloid plaque a) deposition, b) persistence and/or c) dissolution and clearance in brain. The major objectives of this Phase II SBIR proposal are to 1) further determine the mechanisms of action involving heparan sulfate proteoglycans/ glycosaminoglycans in the in vitro formation of amyloid plaques of Alzheimer's and prion diseases, 2) to further develop a non-transgenic animal model of amyloid plaque persistence in vivo, and 3) to develop new in vitro and animal model screening assays for the identification of anti-amyloid plaque therapeutics. The studies described will further establish in vitro screening and non-transgenic animal modeling technologies for the identification of new compounds that target amyloid plaque accumulation as it pertains to AD and prion diseases.
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