CRP, inflammation, and neurodegeneration during aging

描述（由申请方提供）：本修订提案（R21 AG 025496）旨在开发新的小鼠模型，以了解C反应蛋白（CRP）的神经生物学和神经病理学。血液CRP是炎症反应期间检测到的主要急性期反应物，是首次或复发性冠状动脉事件的可靠风险预测因子。CRP升高也与脑缺血有关，可能是阿尔茨海默病（AD）和血管性痴呆的一个促成因素。由于炎症过程在血管疾病的老化、AD中是活跃的，我们假设CRP升高将加速正常脑老化过程中的胶质细胞活化，并将加剧AD样变化。将使用具有慢性CRP升高（全身性或神经元特异性）的转基因小鼠模型评价该假设。我们提出四个目标：目标1：使用现有的CRP过表达小鼠（huCRPtg），确定慢性升高的血液人CRP（huCRP）对正常脑老化期间胶质细胞活化的影响。目标二：构建神经元特异性表达转基因huCRP的小鼠（neuron-huCRPtg）目的3：研究huCRP升高对年轻neuron-huCRPtg小鼠脑病变的影响。目的4：研究hu CRP升高在现有AD转基因小鼠（APPswe/ind）中的作用，这些小鼠快速积累A β-淀粉样蛋白沉积。F1杂种将使用APPswe/ind和现有的全身性huCRPtg（Y1）以及神经元特异性huCRPtg（如可用）制备。将检查F1杂种的A β-淀粉样蛋白沉积的变化。

DESCRIPTION (provided by applicant): This revised proposal (R21 AG025496) aims to develop new mouse models to understand the neurobiology and neuropathology of C-reactive protein (CRP). Blood CRP, the major acute phase reactant detected during an inflammatory response, is a robust risk predictor for first-ever or recurrent coronary events. CRP elevation is also associated with cerebral ischaemia and may be a contributing factor in Alzheimer disease (AD) and vascular dementia. Because inflammatory processes are active in aging, AD, in vascular disease, we hypothesize that CRP elevations will accelerate glial activation during normal brain aging and will intensify AD-like changes. This hypothesis will be evaluated with transgenic mouse models which have chronic CRP elevations, either systemically or specifically in neurons. We propose four aims: Aim 1: Determine effects of chronically elevated blood human CRP (huCRP) on glial activation during normal brain aging, using existing CRP overexpressing mice (huCRPtg). Aim 2: Construct mice with neuron-specific expression of transgenic huCRP (neuron-huCRPtg) Aim 3: Study contribution of huCRP elevations to brain lesions in young neuron-huCRPtg mice. Aim 4: Study contribution of hu CRP elevations in existing AD transgenic mice (APPswe/ind) that rapidly accumulate deposits of Abeta-amyloid. F1 hybrids will be made with APPswe/ind and the existing systemic huCRPtg (Y1) and with the neuron-specific huCRPtg (when available). The F1 hybrids will be examined for changes in deposits of Abeta-amyloid.