Alzheimer's Amyloid Plaque Persistence In Vivo

描述（由申请人提供）：阿尔茨海默病（AD）是一种退行性疾病， 临床上表现为记忆力逐渐丧失的脑部疾病， 认知，推理，判断和情绪稳定，逐渐导致 严重的精神恶化最终死亡AD是导致 老年痴呆症，今天影响4-5百万美国人，这是 预计在未来25年内发病率会翻倍。AD的特征在于 不溶性纤维状淀粉样蛋白沉积物的脑积累， β-淀粉样蛋白（AB），无论是作为细胞外淀粉样斑块在大脑中 实质或血管壁中。AB淀粉样蛋白形成、沉积和 据信，脑中的持久性在AD发病机制中起核心作用， 导致神经元丢失和记忆功能障碍，因此已经成为 是开发治疗AD新药的中心目标， 相关疾病。在AD中，目前没有治愈或实质上有效的方法。 治疗，患者通常在3-10年内死亡。. 我们的第一阶段SBIR研究已经确定了高度 硫酸化糖胺聚糖和相关大分子 诱导马耳他交叉嗜酸性淀粉样蛋白斑块样沉积， 在形态和超微结构上与那些淀粉样蛋白 来自AD脑的斑块。利用这项技术，我们已经开始开发 体外筛选技术和一种新的非转基因淀粉样蛋白啮齿动物模型 斑块沉积和持续性，用于快速识别 靶向淀粉样斑块的潜在抗淀粉样斑块治疗剂a） 沉积，B）持久性和/或c）在脑中溶解和清除。的 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聚糖的作用机制/ 糖胺聚糖在阿尔茨海默氏症淀粉样斑体外形成中的作用 和朊病毒疾病，2）进一步开发非转基因动物模型， 淀粉样斑块在体内的持久性，以及3）开发新的体外和动物 用于鉴定抗淀粉样蛋白斑的模型筛选测定 治疗学 所描述的研究将进一步建立体外筛选， 非转基因动物模型技术用于鉴定新的 靶向淀粉样蛋白斑块积累的化合物，因为它与AD有关， 朊病毒疾病 拟议商业应用：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