Vascular inflammation and neurotoxicity in aging brain

描述（由申请人提供）：尽管事实上许多神经退行性疾病是与年龄相关的疾病，但衰老如何使中枢神经系统易患神经退行性病变尚未得到充分解决。许多研究已经证明，在神经退行性疾病中炎症蛋白增加。然而，炎症介质的年龄相关变化是否与年龄相关疾病进展有因果关系尚不清楚。我们的实验室已经证明，在阿尔茨海默病中，促炎的脑血管系统释放神经毒素，并可能导致神经元细胞死亡。我们的假设是，脑血管中与年龄相关的炎症变化导致了大脑中与年龄相关的病理。由于神经元细胞死亡是年龄相关的神经退行性疾病的中心病变，我们假设一系列事件将年龄相关的炎症增加与血管介导的神经元细胞死亡联系起来。目的1-确定炎症蛋白的表达是否随着年龄的增长而增加。Fischer 344大鼠在6、12、18和24月龄时被用来确定在没有疾病的情况下，衰老是否影响炎症细胞因子（il -1 β、IL-6、IL-8、tnf - α）和趋化因子（RANTES、MCP-1、mip1 - α）的血管表达。通过ELISA、western和Northern blots、real-time PCR和RT-PCR在离体脑微血管中检测炎症蛋白，并对组织切片进行免疫组化。目的2-确定年龄相关的炎症变化是否与血管介导的神经细胞死亡有因果关系。我们的模型预测，在衰老过程中，大脑中的血管炎症有助于损伤后血管介导的神经元细胞死亡。使用体内和体外损伤模型和血管介导的神经元细胞死亡评估Fischer 344大鼠在6、12、18和24个月时暴露于脂质或氧化应激下的脑微血管。在损伤前给予抗炎药物是用来确定抑制炎症是否能阻止神经毒性因子的释放。这些结果将首次确定与年龄相关的炎症变化与血管介导的神经元细胞死亡之间的机制级联。这个项目的结果可能突出了迄今为止未被认识到的衰老方面，并表明旨在减少血管炎症和维持脑血管功能的方法可能对成功的大脑衰老很重要。

DESCRIPTION (provided by applicant): Despite the fact that many neurodegenerative diseases are age-related disorders, how aging predisposes the CNS to the development of neurodegenerative pathologies has not been adequately addressed. Numerous studies have documented an increase in inflammatory proteins in neurodegenerative diseases. However, whether age-related changes in inflammatory mediators are causally-linked to age-related disease progression is unknown. Our laboratory has shown that in Alzheimer's disease a pro-inflammatory cerebral vasculature releases neurotoxins and likely contributes to neuronal cell death. It is our hypothesis that age-related inflammatory changes in brain blood vessels contribute to age-related pathology in the brain. Because neuronal cell death is a central lesion in age-associated neurodegenerative diseases, we postulate a chain of events linking age-related increases in inflammation with vascular-mediated neuronal cell death. Aim 1- To determine if expression of inflammatory proteins increases in the cerebral vasculature with age. Fischer 344 rats at 6,12, 18, and 24 months of age are used to determine whether aging, in the absence of disease, affects vascular expression of inflammatory cytokines (IL-1beta, IL-6, IL-8, TNF-alpha) and chemokines (RANTES, MCP-1, MIP1-alpha). Inflammatory proteins are determined by ELISA, western and Northern blots, and real-time PCR and RT-PCR in isolated brain microvessels and by immunohistochemistry on tissue sections. Aim 2- To determine if age-related inflammatory changes are causally-linked to vascular mediated neuronal cell death. Our model predicts that in aging-vascular inflammation in the brain contributes to vascular-mediated neuronal cell death after injury. The cerebral microvasculature of Fischer 344 rats at 6,12,18, and 24 months is exposed to lipid or oxidative stress using both in vivo and in vitro injury models and vascular-mediated neuronal cell death assessed. Administration of anti-inflammatory drugs prior to injury is used to determine whether inhibiting inflammation prevents release of neurotoxic factors. These results would, for the first time, identify a mechanistic cascade linking age-related inflammatory changes to vascular mediated neuronal cell death. Results from this project could highlight a heretofore-unappreciated aspect of aging and suggest that approaches aimed at minimizing vascular inflammation and maintaining brain vascular function could be important for successful brain aging.