Alzheimer's Amyloid Plaque Persistence In Vivo

描述(申请人提供)：阿尔茨海默病(AD)是一种退行性疾病 以记忆力进行性丧失为临床特征的脑部疾病， 认知、推理、判断和情绪稳定，逐渐导致 严重的精神恶化，最终导致死亡。广告是最主要的原因 老年人中的痴呆症，今天影响到400万到500万美国人，这是 预计在未来25年内发病率将翻一番。广告的特点是 脑内不溶纤维淀粉样沉淀物的积聚 β-淀粉样蛋白(AB)，或作为大脑中的细胞外淀粉样斑块 薄壁组织或在血管壁中。AB淀粉样蛋白的形成、沉积和 脑中的持续性被认为在AD的发病机制中起着核心作用 导致神经元丧失和记忆功能障碍，因此成为 开发治疗AD和AD的新药的中心目标 相关的障碍。在AD中，目前没有治愈或基本有效的方法 治疗，病人通常在3-10年内死亡。。 我们的第一阶段SBIR研究已经确定了高度 硫酸氨基葡聚糖及其相关大分子的体外研究 诱导马耳他交配的同源亲和性淀粉样斑块沉积，这是 在形态和超微结构上与淀粉样蛋白惊人地相似 斑块来源于AD脑。利用这项技术，我们已经开始开发 淀粉样蛋白体外筛选技术及新型非转基因啮齿动物模型的建立 斑块沉积和持久性，这是用来快速识别 针对淀粉样斑块a的潜在抗淀粉样斑块疗法) 沉积，b)持久性和/或c)脑内溶解和清除。这个 本第二阶段SBIR提案的主要目标是：1)进一步确定 涉及硫酸乙酰肝素蛋白多糖的作用机制 糖胺多糖在阿尔茨海默病淀粉样斑块体外形成中的作用 和Pron病，2)进一步发展非转基因动物模型 淀粉样斑块在体内的持久性，以及3)在体外和动物中开发新的 模型筛选法用于抗淀粉样斑块的鉴定 治疗学。 所描述的研究将进一步建立体外筛选和 用于鉴定新基因的非转基因动物模型技术 靶向淀粉样斑块堆积的化合物，因为它与AD和 普恩病毒病。 建议的商业应用：不可用

DESCRIPTION (provided by applicant): 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. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE