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: 6234426
• 负责人: BLAS FRANGIONE
• 金额: $ 12.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6234426
• 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.

脑淀粉样蛋白包括一组不同的疾病 临床表达以及不溶性的组成和分布 淀粉样蛋白纤维。 我们相信所有类型的脑淀粉样蛋白涉及 淀粉样前体蛋白的降解改变，该沉积 发生在遗传或以其他方式降解的患者中发生 这些分子。 我们提出了元素的三方部门 发病机理问题的中心：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 微环境组织因子可能有助于促进 前体蛋白进入其不溶性淀粉样产品。 最近，我们表明零星大脑的淀粉样蛋白原纤维 淀粉样蛋白血管病和一种常染色体主导形式的家族性淀粉样蛋白 荷兰起源患者的血管病（也指定为遗传性脑 荷兰类型的淀粉样变性出血）类似于阿尔茨海默氏病 淀粉样β-蛋白质（ABETA）。 这些发现表明Abeta 沉积障碍构成了重叠的临床病理范围 范围从主要血管受累的患者范围 对于有血管和实质参与的患者 各种比例，临床上的中风和痴呆症表现出来， 分别。 我们还发现这些疾病表现出不同 神经斑块状结构或“前叶蛋白病变”，表明 它们代表了β-蛋白沉积的早期阶段。 类似的淀粉样蛋白 在神经学上，通常会遇到沉积物 无症状的年龄个体；因此，重要的是要澄清他们 关系。 我们提出：1）生化和免疫组织化学分析 从HCHWA和家族性的荷兰患者获得的前叶纤维病变以及 广告的零星形式。 2）淀粉样蛋白和其他的表征 来自AD的家族和零星形式的组成部分。 3）执行相似 转基因小鼠的研究。 这项研究与理解 与淀粉样蛋白沉积相关的基本疗法机制 衰老，淀粉样血管病和阿尔茨海默氏病；它可能对 病理和临床水平的诊断目的 治疗干预。