Temporal, Spatial and Cellular Dynamics of Amyloid Plaque Deposition

淀粉样蛋白斑沉积的时间、空间和细胞动力学

• 批准号: 10525630
• 负责人: Charles G. Glabe
• 金额: $ 226.15万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525630
• 关键词: Aducanumab; Alzheimer' s Disease; Amino Acids; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Amyloid deposition; Antibodies; Astrocytes; Axon; Axonal Transport; Biochemical; Brain; Brain region; Cells; Chemistry; Clinical; Cognitive; Cre driver; Deposition; Diffuse; Diffusion; Disease; Economics; Elements; Epidemic; Excision; FDA approved; Failure; Fluorescence; Goals; Investigation; Kinetics; Label; Location; Mediating; Microglia; Modeling; Morphology; Mouse Cell Line; Nerve Degeneration; Neurites; Neurodegenerative Disorders; Neurons; Oligodendroglia; Outcome; Pathogenesis; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Physiologic pulse; Placebos; Population; Process; Proteins; Proteome; Senile Plaques; Series; Societies; Standard Model; Structure; Synapses; Technology; Testing; Time; Transgenic Model; base; burnout; cell type; cerebrovascular amyloid; drug discovery; experimental study; extracellular; insight; monomer; neuronal cell body; prevent; targeted treatment; therapeutic development

Project Summary Amyloid plaques are one of the canonical pathological hallmarks of Alzheimer's disease (AD). The amyloid hypothesis is a standard model for amyloid Abeta pathogenesis that has driven drug discovery for the past 25 years, giving rise to many clinical failures, including drugs that make the treated patients cognitively worse than the placebo-treated controls. Aducanumab (Aduhelm) is the first disease modifying treatment recently approved by the FDA on the basis of its ability to facilitate the removal of amyloid plaques, indicating the importance of these strictures. There are several different types of plaques and amyloid deposits known in AD, including diffuse, “classical” “dense core”, neuritic plaques and cerebrovascular amyloid (CVA) and intraneuronal amyloid deposits. While there is much that is known about amyloid plaque morphology and composition in AD, less is known about mechanisms of plaque deposition, their dynamics and interrelationships, the contributions of different cell types to their formation and their significance for AD pathogenesis. We seek to investigate these critical aspects of amyloid plaque deposition in a detailed and un unbiased fashion by labeling the proteome of specific cell types with the non-canonical amino acid, azidonorleucine, and following the incorporation of ANL-labeled proteins into amyloid deposits. The goal of this proposal is to determine the temporal, spatial and cellular dynamics of amyloid deposition using cutting-edge biorthogonal non-canonical amino acid tagging (BONCAT) technology and specific Cre driver mouse lines for cell specific synthesis of clickable proteins, exploiting click chemistry for fluorescence localization (FUNCAT), purification and enrichment and biochemical analysis. Our central hypothesis is that different types of plaques are deposited by different mechanisms at different times and locations by different populations neurons and that some of these types of plaques may be mechanistically unrelated to the other types of amyloid and may be differentially associated with pathogenesis and neuronal degeneration.

项目摘要 淀粉样斑块是阿尔茨海默病（AD）的典型病理标志之一。 淀粉样蛋白假说是淀粉样蛋白Abeta发病机制的标准模型， 在过去的25年里，药物发现，导致许多临床失败，包括药物， 使接受治疗的患者的认知能力比接受安慰剂治疗的对照组差。aducanumab （Aduhelm）是FDA最近批准的第一种疾病修饰治疗， 它的能力，以促进淀粉样斑块的清除，表明这些的重要性， 狭窄在AD中已知有几种不同类型的斑块和淀粉样蛋白沉积， 包括弥漫性、"典型"、"致密核心"、神经炎斑块和脑血管淀粉样蛋白（CVA） 和神经元内淀粉样沉积。虽然对淀粉样斑块有很多了解， 形态和组成的AD，了解较少的机制，斑块沉积，其 动力学和相互关系，不同细胞类型对其形成的贡献， 对AD发病机制的意义。我们试图研究淀粉样蛋白的这些关键方面， 通过标记特定细胞的蛋白质组， 型与非规范氨基酸，叠氮正亮氨酸，并随后纳入 ANL标记的蛋白质转化为淀粉样沉积物。本提案的目的是确定 淀粉样蛋白沉积的时间、空间和细胞动力学 非规范氨基酸标记（BONCAT）技术和特异性Cre驱动小鼠系， 细胞特异性合成可点击蛋白质，利用点击化学荧光 定位（FUNCAT）、纯化和富集以及生化分析。我们的中央 假设不同类型的斑块是由不同的机制在不同的时间沉积的， 不同群体神经元的时间和位置，其中一些类型的斑块 可能与其他类型的淀粉样蛋白在机制上无关， 与发病机制和神经元变性有关。