TRANSGENIC MODELS TO SUDY ALZHEIMERS DISEASE

研究阿尔茨海默病的转基因模型

• 批准号: 2636026
• 负责人: Lennart Mucke
• 金额: $ 39.41万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2636026
• 关键词: Alzheimer's disease; amyloid proteins; apoptosis; behavioral /social science research tag; disease /disorder model; gene induction /repression; genetic promoter element; genetically modified animals; human genetic material tag; laboratory mouse; model design /development; neurons; neuropharmacology; neuropsychological tests; neurotoxins; nucleic acid sequence; platelet derived growth factor; protein biosynthesis; tissue /cell culture

DESCRIPTION Alzheimer's disease (AD) is characterized clinically by dementia and neuropathologically by amyloid plaques, amyloid angiopathy, dystrophic neurites, NFT's, gliosis, and loss of neuronal subpopulations and synapses. Increasing evidence suggests that the AB peptide derived from APP plays a central role in AD. The goals of this project are to characterize neuronal and glial products that contribute to amyloidogenesis and neurodegeneration and identify cortical AD-related pathogenetic pathways that could be targeted by therapeutic interventions. Mice expressing a PDGF-promoter driven, alternatively spliced hAPP minigene, (PDGF-APP mice) develop several aspects of AD neuropathology. This proposal is to utilize this and related models to study cerebral amyloidogenesis and amyloid-induced neurodegeneration in vivo with the following aims: 1) Determine what factors influence AB production and B-amyloid deposition in vivo.; 2) Determine whether development of neuronal/synaptic degeneration in PDGF-hAPP mice depends on B-amyloid formation; 3) Determine whether B-amyloid in the brain results in aberrant induction of neuronal apoptosis and whether this process involves excitotoxic mechanisms.

描述 阿尔茨海默病 (AD) 的临床特征是痴呆 以及神经病理学上的淀粉样斑块、淀粉样血管病、营养不良 神经突、NFT、神经胶质增生以及神经元亚群和突触的丧失。 越来越多的证据表明，源自 APP 的 AB 肽发挥着重要作用。 AD 中的核心作用。 该项目的目标是表征神经元 和神经胶质产物有助于淀粉样蛋白生成和神经变性 并确定与皮质 AD 相关的发病途径 治疗干预的目标。 表达 PDGF 启动子的小鼠 驱动的、选择性剪接的 hAPP 小基因（PDGF-APP 小鼠）发育出多种 AD 神经病理学的各个方面。 本提案旨在利用此及相关 研究脑淀粉样蛋白生成和淀粉样蛋白诱导的模型 体内神经变性的目的如下：1）确定什么 影响体内 AB 产生和 B-淀粉样蛋白沉积的因素。 2） 确定 PDGF-hAPP 中是否发生神经元/突触变性 小鼠依赖于 B-淀粉样蛋白的形成； 3) 确定是否存在B-淀粉样蛋白 大脑导致神经元细胞凋亡的异常诱导，以及这是否 过程涉及兴奋性毒性机制。