TRANSGENIC MODELS TO SUDY ALZHEIMERS DISEASE

研究阿尔茨海默病的转基因模型

• 批准号: 6167881
• 负责人: Lennart Mucke
• 金额: $ 39.37万
• 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/6167881
• 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)的临床特征是痴呆症 以及由淀粉样斑块、淀粉样血管病、营养不良引起的神经病理改变 神经突起、神经纤维母细胞瘤、神经胶质增生症，以及神经元亚群和突触的丢失。 越来越多的证据表明，来自APP的AB肽在 在AD中的核心作用。这个项目的目标是描述神经元的特征。 以及有助于淀粉样变和神经退行性变的神经胶质产物 并确定可能与皮质AD相关的致病途径 作为治疗干预的目标。表达PDGF启动子的小鼠 驱动、选择性剪接的Happ微型基因(PDGF-APP小鼠)发展出几个 阿尔茨海默病的神经病理学方面。这项建议是利用这一点和相关的 研究脑淀粉样蛋白发生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AB产生和体内B-淀粉样蛋白沉积的因素；2) 确定PDGF-HAPP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B-淀粉样蛋白在 大脑导致神经细胞凋亡的异常诱导以及这是否 这一过程涉及兴奋性毒性机制。