THE BIOCHEMISTRY OF BRAIN AMYLOIDS AND PREAMYLOID LESIONS

脑淀粉样蛋白和前淀粉样蛋白病变的生物化学

• 批准号: 6098460
• 负责人: BLAS FRANGIONE
• 金额: $ 13.14万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6098460
• 关键词: Alzheimer's disease; Downs syndrome; aging; amyloid proteins; amyloidosis; antibody formation; autosomal dominant trait; brain; cerebral hemorrhage; chemical cleavage; fluorescence microscopy; genetically modified animals; histopathology; human tissue; immunocytochemistry; immunoelectron microscopy; laboratory mouse; laboratory rabbit; neuritic plaques; postmortem; protein purification; protein sequence; proteolysis; synthetic peptide; western blottings

Brain amyloidoses comprise a heterogeneous group of diseases that vary in clinical expression and the composition and distribution of insoluble amyloid fibrils. We believe that all types of cerebral amyloids involve altered degradation of an amyloid precursor protein, and that deposition occurs in patients who are genetically or otherwise defective in degrading these molecules. We put forward a tripartite division of the elements central to the issue of pathogenesis: the inherent chemical amyloidogenic potential of the precursor protein; the possibility of aberrant protein metabolism and/or genetic variants, and the existence of disease microenvironmental tissue factors that may facilitate the conversion of precursor proteins into their insoluble amyloid products. Recently we have shown that the amyloid fibrils of sporadic cerebral amyloid angiopathy and an autosomal dominant form of familial amyloid angiopathy in patients of Dutch origin (also designated Hereditary Cerebral Hemorrhage with Amyloidosis of Dutch Type) are similar to Alzheimer Disease amyloid beta-protein (Abeta). These findings indicate that Abeta deposition disorders form a spectrum of overlapping clinico-pathological conditions which range from patients with predominant vascular involvement to patients having a combination of vascular and parenchyma involvement in varying proportions, manifested clinically by stroke and dementia, respectively. We have also found that these disorders exhibit varying neuritic plaque-like structures, or "preamyloid lesions", suggesting that they represent an early stage of beta-protein deposition. Similar amyloid deposits are often encountered in a significant percent of neurologically asymptomatic aged individuals; hence it is important to clarify their relationship. We propose: 1) the biochemical and immunohistochemical analysis of preamyloid lesions obtained from Dutch patients with HCHWA and familial and sporadic forms of AD. 2) the characterization of amyloid protein and other components from familial and sporadic forms of AD. 3) performing similar studies in transgenic mice. This study is relevant for understanding the basic etiopathogenetic mechanisms associated with amyloid deposition in aging, amyloid angiopathy, and Alzheimer's Disease; it may be useful for diagnostic purposes at a pathological and clinical level and for therapeutic intervention.

脑淀粉样变性包括一组异质性疾病， 临床表现和不溶性成分及分布 淀粉样纤维 我们认为所有类型的大脑淀粉样蛋白都涉及 淀粉样前体蛋白的降解改变， 发生在基因或其他方面有缺陷的患者中， 这些分子。 我们提出了一个三分要素 发病机制的核心问题：固有的化学淀粉样蛋白生成 前体蛋白的潜力;异常蛋白的可能性 代谢和/或遗传变异，以及疾病的存在 微环境组织因素，可能有助于转换 前体蛋白转化为不溶性淀粉样蛋白产物。 最近，我们发现散发性脑梗死的淀粉样纤维 淀粉样血管病和家族性淀粉样常染色体显性遗传 荷兰籍患者的血管病（也称为遗传性脑血管病 荷兰型淀粉样变性出血）与阿尔茨海默病相似 淀粉样β蛋白（Abeta）。 这些发现表明，Abeta 沉积障碍形成一系列重叠的临床-病理 从主要血管受累的患者 对于同时累及血管和实质的患者， 不同比例，临床表现为中风和痴呆， 分别 我们还发现，这些疾病表现出不同的 神经炎斑块样结构，或“类神经胶质病变”，表明， 它们代表β-蛋白沉积的早期阶段。 类淀粉样蛋白 在神经系统疾病中， 无症状的老年人;因此，重要的是要澄清他们的 关系 我们建议：1）生化和免疫组化分析， 从患有HCHWA的荷兰患者和家族性和 零星的AD。 2)淀粉样蛋白和其它蛋白质表征 来自家族性和散发性AD形式的组分。 3)执行类似 转基因小鼠的研究。 这项研究有助于了解 与淀粉样蛋白沉积相关的基本发病机制 衰老、淀粉样血管病和阿尔茨海默病;它可能对 病理学和临床水平的诊断目的， 治疗干预