TRANSGENIC MICE, INFLAMMATION & THE ALZHEIMER PHENOTYPE

转基因小鼠，炎症

• 批准号: 6169195
• 负责人: MARCIA N GORDON
• 金额: $ 16.02万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2002-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6169195
• 关键词: Alzheimer's disease; amyloid proteins; animal breeding; complement deficiency; complement pathway; gene expression; genetic strain; genetically modified animals; immunocytochemistry; immunologic assay /test; inflammation; interleukin 1; laboratory mouse; lipopolysaccharides; model design /development; phenotype; presenilin

This application describes a new transgenic mouse model for the study of Abeta amyloid deposition in brain, and the pathological consequences of amyloid deposition. These mice derive from a cross between Tg2576, a line expressing a mutant form of the human amyloid precursor protein gene (APP), and M146L5.1, a line expressing a mutant form of the human presenilin-1 gene (PS1). Like other transgenic lines overexpressing APP, these mice do not exhibit detectable neurodegeneration, nor is the inflammatory reaction in these mice similar to that found in Alzheimer's disease (AD) brain. In this manner the transgenic mice resemble the 5 percent of nondemented elderly individuals who exhibit substantial Abeta amyloid plaque pathology at autopsy (referred to as high plaque normals or high pathology controls). One surprising feature of mouse immunity is a relative lack of complement activity compared to other species (including humans). Increasing evidence suggests that the reaction between fibrillar Abeta and complement (specifically component C1q) integrally participates in an inflammatory cascade cycle that ultimately leads to bystander effects on neural tissue. The hypothesis tested in this proposal is that low levels of complement activation by Abeta, either due to insufficient quantities of complement, or qualitative differences in the structure of human and murine complement, limits the extent of the AD phenotype expressed by the transgenic mice. To test this hypothesis, doubly transgenic mice will a) be bred into a mouse strain that has relatively high levels of complement activity, b) the innate immune system will be directly activated with LPS or IL-1 infusions or c) supplemented with human C1q. The degree to which these manipulations enhance the manifestation of the AD phenotype will be evaluated by immunocytochemistry and immunoassay.

该应用描述了一种新的转基因小鼠模型，用于研究大脑中淀粉样蛋白的沉积以及淀粉样蛋白沉积的病理后果。 这些小鼠源自TG2576之间的交叉，这是一种表达人淀粉样蛋白前体蛋白基因（APP）和M146L5.1的线形式的线，这是一种表达人Presenilin-1基因突变形式的线（PS1）。像其他过表达应用的转基因线一样，这些小鼠也不表现出可检测的神经变性，这些小鼠的炎症反应也不类似于阿尔茨海默氏病（AD）脑（AD）大脑中的炎症反应。 以这种方式，转基因小鼠类似于尸检时表现出大量Abeta淀粉样蛋白斑块病理学的5％的非注重老年人（称为高斑块正常或高病理控制）。小鼠免疫力的一个令人惊讶的特征是与其他物种（包括人类）相比，相对缺乏补体活性。越来越多的证据表明，纤维状ABETA与补体（特别是组分C1Q）之间的反应集成参与了炎症级联周期，最终导致旁观者对神经组织的影响。 在该提案中检验的假设是，由于不足的补体或人类和鼠补体结构的质量差异，ABETA的补体较低激活限制了转基因小鼠表达的AD表型的程度。 为了检验这一假设，双重转基因小鼠将a）繁殖成具有相对较高水平的补体活性的小鼠菌株，b）先天免疫系统将直接用LPS或IL-1输注或C）补充人类C1q。 这些操作增强AD表型表现的程度将通过免疫细胞化学和免疫测定法进行评估。