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.

脑淀粉样变性包括一组不同类型的疾病