ALZHEIMER'S AMYLOID PLAQUE PERSISTENCE IN VIVO

点击翻译按钮获取中文摘要

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 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. Over the last few years, our studies have determined that other additional factors, such as specific heparan sulfate proteoglycans (i.e. perlecan), are necessary for the formation and persistence of "fibrillar" Abeta deposits in AD brain. Use of purified perlecan has established a consistent rodent model for the rapid deposition, and persistence of Abeta amyloid in brain. 1 or 2- week infusions of Abeta + perlecan into hippocampus leads to congophilic amyloid deposits in 80 of 80 animals (100%), in comparison to 41 of 70 (58.5%) following infusions of Abeta alone. Perlecan contributes to the long- term persistence of Abeta amyloid in brain and the formation of cerebrovascular amyloid deposits, not observed following Abeta infusions. We have now significantly advanced this animal model by implementing new proprietary protocols to induce the in vitro formation of maltese-cross congophilic amyloid plaque-like deposits, which are morphologically and ultrastructurally similar to those amyloid plaque cores derived from AD brain. New animal modeling methodologies can be used for the rapid in vivo identification of 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 I proposal are 1) to determine the role of proteoglycans/ GAGs on amyloid plaque formation, and 2) to determine anatomical and molecular consequences of "amyloid plaque", "fibrillar" Abeta persistence, and cerebrovascular amyloid deposition in brain. The studies described will further establish a consistent animal model for Abeta amyloid plaque deposition and persistence, and will allow (in a phase II proposal) for the rapid screening of new potential therapeutic candidates to treat Abeta plaque amyloidosis in AD. PROPOSED COMMERCIAL APPLICATIONS: Alzheimer's disease (AD) currently affects 4-5 million Americans, at an estimated costs of $80-$100 billion. Currently, there is no cure or effective treatment, and the patient usually dies within 3-10 years from disease onset. New animal models which can be implemented to rapidly test the efficacy of anti-Abeta amyloid therapeutics are desperately needed. We have discovered new methods to consistently form Alzheimer's amyloid plaque-like deposits in a test tube, and are establishing a new animal model of amyloid plaque persistence in vivo. This model can be utilized to rapidly screen for new anti- amyloid plaque therapeutics in the future.