Vascular inflammation and neurotoxicity in aging brain

描述(申请人提供)：尽管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于发生神经退行性病理还没有得到充分的研究。许多研究证明，在神经退行性疾病中，炎性蛋白增加。然而，年龄相关的炎症介质的变化是否与年龄相关的疾病进展有关尚不清楚。我们的实验室已经证明，在阿尔茨海默病中，一种促炎症的脑血管会释放神经毒素，并可能导致神经细胞死亡。我们的假设是，与年龄相关的脑血管炎症变化有助于大脑中与年龄相关的病理。由于神经细胞死亡是年龄相关神经退行性疾病的中心损害，我们假设一系列事件将与年龄相关的炎症增加与血管介导的神经细胞死亡联系起来。目的1-确定炎性蛋白在脑血管中的表达是否随年龄增长而增加。使用6、12、18和24月龄的Fischer 344大鼠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-1β、IL-6、IL-8、TNF-α)和趋化因子(RANTES、MCP-1、MIP1-α)的血管表达。采用ELISA法、免疫印迹法、实时荧光定量聚合酶链式反应和逆转录-聚合酶链式反应以及组织切片免疫组织化学方法检测炎性蛋白。目的2-确定与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联系。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细胞死亡。使用体内和体外损伤模型和血管介导的神经细胞死亡评估，对6、12、18和24个月龄的Fischer 344大鼠的脑微血管系统暴露于脂质或氧化应激。在损伤前给予抗炎药物用于确定抑制炎症是否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细胞死亡之间的机制级联。该项目的结果可能会突显衰老的一个迄今未被认识的方面，并表明旨在最大限度地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非常重要。

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.