Alzheimer Mouse Model for Intraneuronal Amyloid-Beta Oligomer Biology

用于神经元内淀粉样蛋白-β寡聚体生物学的阿尔茨海默病小鼠模型

• 批准号: 8195552
• 负责人: SAMUEL E. GANDY
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195552
• 关键词: Age; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Appearance; Attention; Behavior assessment; Behavioral; Biochemical; Biology; Brain; Cerebral Amyloid Angiopathy; Dementia; Deposition; Development; Exons; Freedom; Functional disorder; Gender; Genes; Genetic; Hippocampus (Brain); Histopathology; Impaired cognition; Incidence; Learning; Life; Longevity; Mediator of activation protein; Memory; Modeling; Mus; Neurons; Pathology; Performance; Pharmaceutical Preparations; Population; Prevalence; Proteins; Senile Plaques; Severities; Sorting - Cell Movement; Structure; Synaptophysin; System; Testing; Time; Transgenic Mice; Transgenic Organisms; Traumatic Brain Injury; Variant; Veterans; World War II; age related; human very old age (85+); immunoreactivity; in vivo; intraneuronal beta amyloid; morphometry; morris water maze; mouse model; mutant; neuropathology; operation; overexpression; presenilin; prevent; promoter; public health relevance

Project summary Recently, much attention has turned to the study of so-called "oligomeric" forms of the amyloid beta peptide (A¿)) as possible key mediators of dementia in Alzheimer's disease. We have chosen to exploit the propensity of Dutch A¿ to form oligomers is order to create a transgenic mouse model of the biochemical pathology, neuropathology, and behavioral pathology of neuronally-derived A¿ oligomers by overexpressing Dutch APP on the Thy1 promoter (Thy1-Dutch APPE693Q transgenic mouse line). In preliminary characterization of these Thy1-Dutch APPE693Q mice, we have observed aging-dependent cognitive decline and a number of quantifiable neuropathological changes. However, in our hands, Thy1-APPE693Q mice never develop parenchymal amyloid deposits of any sort during their lifespan; however, immunodetectable A¿ oligomers accumulate, and these oligomers appear to be localized to the neuronal endosomal-lysosomal system. In order to generate A¿ histopathology, we have crossed the Thy1- Dutch APPE693Q mice with familial Alzheimer's mutant presenilin lacking exon 9 (PS1¿9). This pathogenic mutant form of PS1 elevates levels of A¿42, thereby causing plaques to form in bigenic mice (these mice are designated Thy1-Dutch APPE693Q x PS1¿9 bigenics). However, while the mutant PS1 causes plaques to form, the appearance of amyloid plaques has no obvious effect on the time course or initial severity of cognitive decline. In summary, we observe: (1) accumulation of intraneuronal APP/A¿ derivatives in single Dutch APP transgenic and bigenic PS/APP mice; and (2) accumulation of Dutch CAA. For this MERIT application, we propose to perform quantitative characterization of single Dutch APP transgenic and bigenic PS/APP mice, according to gender and at various ages over their lifespans, using (a) Assessment of behavioral performance in the Morris water maze and inhibitory avoidance models of spatial learning and memory; (b) Quantification of brain levels of APP, ¿ and ¿ CTFs, A¿40, A¿42, A¿ oligomers, and synaptophysin; (c) Subcellular localization of APP-A¿-like immunoreactivity, including Dutch CAA; (d) Quantitative morphometry to determine integrity of hippocampal neuronal populations and to estimate intraneuronal A¿ burden. The availability of lines of mice that are impaired by oligomers and never develop amyloid plaques would greatly facilitate the construction of in vivo efficacy screens in the search for anti- oligomer drugs for the treatment of Alzheimer's disease.

项目总结 最近，许多注意力都转向了对所谓的低聚形式的 淀粉样β蛋白(A？)可能是阿尔茨海默病痴呆的关键介质。我们 选择利用荷兰人形成低聚物的倾向是为了创造一个 转基因小鼠的生化病理学、神经病理学和行为学模型 Thy1上过表达荷兰APP的神经源性A？寡聚体的病理学研究 启动子(Thy1-荷兰APPE693Q转基因小鼠)。在对这些的初步描述中 Thy1-荷兰APPE693Q小鼠，我们观察到了与年龄相关的认知功能下降和一些 可量化的神经病变。然而，在我们手中，Thy1-APPE693Q小鼠 在它们的生命周期内形成任何类型的实质淀粉样沉积；然而， 免疫可检测到的A型寡聚体聚集，这些寡聚体似乎定位于 神经元内体-溶酶体系统。为了产生一种组织病理学，我们有 Thy1-荷兰APPE693Q小鼠与家族性阿尔茨海默病突变体早老素缺乏外显子杂交 9(PS1？9)。PS1的这种致病突变形式提高了A？42的水平，从而导致 在双基因小鼠中形成斑块(这些小鼠被命名为Thy1-Dutch APPE693Q x PS1？9 重男轻女)。然而，当突变体PS1导致斑块形成时，淀粉样蛋白的出现 斑块对认知功能下降的时间进程或初始严重程度没有明显影响。 综上所述，我们观察到：(1)神经元内APP/A派生物在单个 荷兰APP转基因和双基因PS/APP小鼠；(2)荷兰CAA蓄积。为了这个 优点应用程序，我们建议对单个荷兰应用程序进行量化表征 转基因和双基因PS/APP小鼠，根据性别和不同年龄 寿命，使用(A)评估Morris水迷宫和 空间学习和记忆的抑制性回避模型；(B)大脑水平的量化 APP和CTF、A？40、A？42、A？寡聚体和突触素；(C)亚细胞定位 APP-A？样免疫反应，包括荷兰CAA；(D)定量形态计量 确定海马神经元群的完整性并估计神经元内A值 负担。 受低聚物损害且从未发生淀粉样蛋白的小鼠品系的可用性 斑块将极大地促进体内药效筛选的建立，以寻找抗- 治疗阿尔茨海默病的低聚药物。