AMYLOID DEPOSITION IN ALZHEIMER'S DISEASE

阿尔茨海默病中的淀粉样蛋白沉积

• 批准号: 6168061
• 负责人: PETER T LANSBURY
• 金额: $ 25.32万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-07-12 至 2001-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168061
• 关键词: Alzheimer's disease; amyloid proteins; amyloidosis; apolipoproteins; chemical binding; chemical kinetics; chemical structure function; conformation; dichroism; disulfide bond; electron microscopy; glycoprotein biosynthesis; glycoprotein structure; infrared spectrometry; inhibitor /antagonist; interferometry; mutant; neuritic plaques; neurofibrillary tangles; neuropeptides; nuclear magnetic resonance spectroscopy; polymerization; protein structure function; stress proteins; synthetic peptide

DESCRIPTION: The appearance of amyloid deposits in the brain is the diagnostic biochemical hallmark of Alzheimer's disease. Substantial evidence has accumulated that suggests that amyloid formation leads to neurodegeneration. Since amyloid formation occurs slowly in healthy individuals, it may be the case that it is the rate of formation of amyloid that is the key determinant as to whether an individual will be afflicted. Therefore, the inhibition, or deceleration, of amyloid formation may be a viable therapeutic strategy against Alzheimer's disease. In order to design potential drugs, it is critical to understand the structure of the amyloid deposits and the mechanism of their formation. This proposal focusses on those two issues. Dr. Lansbury has devised a new approach, based on solid-state NMR and Fourier-transform infrared spectroscopy, to determine the three-dimensional structure of amyloid. It is proposed to now apply this methodology for the determination of AD amyloid. Dr. Lansbury has determined that amyloid formation, like a crystallization, follows a nucleation-dependent kinetic pathway. This proposal details efforts to elucidate the details of the kinetic pathway. Dr. Lansbury has shown that apoliprotein E, which has been implicated in AD by genetic studies, inhibits amyloid formation by slowing down the nucleation step. This proposal discusses efforts to determine the precise mode of action of apoE and to relate its structure/conformation to this function. Dr. Lansbury has recently determined that the neuronal peptide NAC is capable of accelerating amyloid formation by a seeding mechanism. Finally, it is hoped that the research will lead to the design of molecules that act as inhibitors of amyloid formation. The structure of these molecules will derive from the ongoing studies of amyloid structure.

描述：脑内淀粉样蛋白沉积