TRANSGENIC MICE, INFLAMMATION & THE ALZHEIMER PHENOTYPE

本申请描述了一种新的转基因小鼠模型，用于研究脑内淀粉样蛋白沉积，以及淀粉样蛋白沉积的病理后果。这些小鼠来自Tg2576和M146L5.1的杂交，Tg2576是表达人类淀粉样蛋白前体蛋白基因（APP）突变形式的细胞系，M146L5.1是表达人类早老素-1基因（PS1）突变形式的细胞系。与其他过表达APP的转基因品系一样，这些小鼠没有表现出可检测到的神经变性，也没有类似于阿尔茨海默病（AD）大脑中的炎症反应。通过这种方式，转基因小鼠类似于5%在尸检中表现出大量β -淀粉样蛋白斑块病理的非痴呆老年人（称为高斑块正常或高病理对照）。与其他物种（包括人类）相比，小鼠免疫力的一个令人惊讶的特征是相对缺乏补体活性。越来越多的证据表明，纤原β和补体（特别是组分C1q）之间的反应完整地参与了炎症级联循环，最终导致神经组织的旁观者效应。本研究的假设是，由于补体数量不足或人与鼠补体结构的质性差异，Abeta激活补体的低水平限制了转基因小鼠表达AD表型的程度。为了验证这一假设，将a)将双转基因小鼠培育成具有相对较高补体活性的小鼠品系，b)通过LPS或IL-1输注直接激活先天免疫系统，或c)补充人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来评估。

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.