CRP, inflammation, and neurodegeneration during aging

描述（由申请人提供）：本修订提案（R21 AG025496）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。由于炎症过程在衰老、AD和血管疾病中都很活跃，我们假设CRP升高会加速正常大脑衰老过程中的神经胶质活化，并加剧AD样变化。这一假设将在具有慢性CRP升高的转基因小鼠模型中进行评估，无论是系统性的还是特异性的神经元。我们提出了四个目标：目的1：利用现有的CRP过表达小鼠（huCRPtg），确定血液中慢性升高的人CRP （huCRP）对正常脑衰老过程中神经胶质活化的影响。目的2：构建神经元特异性表达转基因huCRP （neuron-huCRPtg）的小鼠。目的3：研究huCRP升高对幼年神经元- hucrptg小鼠脑损伤的影响。目的4：研究hu CRP升高对现有AD转基因小鼠（APPswe/ind）快速积累β -淀粉样蛋白沉积的贡献。F1杂交种将由APPswe/ind和现有的系统性huCRPtg （Y1）以及神经元特异性huCRPtg（如有）制成。将检查F1杂交体中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.