CRP, inflammation, and neurodegeneration during aging

描述(申请人提供)：本修订提案(R21AG025496)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。血中的CRP是炎症反应中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强有力的风险预测指标。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和血管疾病中是活跃的，我们假设，在正常脑老化过程中，CRP的升高将加速胶质细胞的激活，并将加剧AD样变化。这一假说将通过转基因小鼠模型进行评估，该模型系统地或特定地在神经元中存在慢性CRP升高。我们提出了四个目标：目的1：利用现有的CRP过度表达小鼠(HuCRPtg)，确定慢性升高的血人CRP(HuCRP)对正常脑老化过程中神经胶质细胞激活的影响。目的2：构建神经元特异性表达的huCRP转基因小鼠(Neuron-huCRPtg)目的3：研究huCRP表达升高对幼年神经元-huCRPtg小鼠脑损伤的影响。目的：研究已有的AD转基因小鼠(APPswe/ind)快速积累Aβ-淀粉样蛋白沉积的HU-CRP升高的作用。将用APPswe/ind和现有的全身性huCRPtg(Y1)和神经元特异性huCRPtg(如果有的话)杂交F1。将对F1杂交后代进行Aβ淀粉样蛋白沉积的变化检查。

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.