Vascular inflammation and neurotoxicity in aging brain

衰老大脑中的血管炎症和神经毒性

• 批准号: 7262461
• 负责人: PAULA GRAMMAS
• 金额: $ 32.52万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7262461
• 关键词: Address; Affect; Age; Age-Months; Aging; Alzheimer' s Disease; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Biochemical; Blood Vessels; Brain; Brain Diseases; CCL2 gene; CXC Chemokines; Cell Death; Central Nervous System Diseases; Cerebrum; Clinical; Defect; Development; Disease; Disease Progression; Enzyme-Linked Immunosorbent Assay; Etiology; Event; Functional disorder; Hyperhomocysteinemia; Hyperlipidemia; IL8 gene; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Injury; Interleukin-6; Laboratories; Lesion; Link; Lipids; Mediating; Mediator of activation protein; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Neurotoxins; Northern Blotting; Oxidative Stress; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Polymerase Chain Reaction; Predisposition; Proteins; Rattus; Reactive Oxygen Species; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Rodent; Testing; Time; Tissues; Tumor Necrosis Factor-alpha; Work; age related; aged; aging brain; base; chemokine; cytokine; human TNF protein; in vivo; insight; juvenile animal; neuron loss; neurotoxic; neurotoxicity; novel; prevent; programs; vascular inflammation

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.

描述（由申请人提供）： 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CNS易于发展为神经退行性病变尚未得到充分解决。许多研究已经证明了神经退行性疾病中炎性蛋白的增加。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因果关系尚不清楚。我们的实验室已经表明，在阿尔茨海默病中，促炎性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有助于大脑中与年龄相关的病理学。由于神经元细胞死亡是与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-确定脑血管中炎症蛋白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，衰老是否影响炎性细胞因子（IL-1 β、IL-6、IL-8、TNF-α）和趋化因子（RANTES、MCP-1、MIP 1-α）的血管表达。通过ELISA、蛋白质印迹和北方印迹以及分离的脑微血管中的实时PCR和RT-PCR以及通过组织切片上的免疫组织化学来确定炎性蛋白。目的2-确定年龄相关的炎症变化是否与血管介导的神经元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，将6、12、18和24个月的Fischer 344大鼠的脑微血管暴露于脂质或氧化应激，并评估血管介导的神经元细胞死亡。在损伤之前施用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一种将年龄相关的炎症变化与血管介导的神经元细胞死亡联系起来的机制级联。该项目的结果可以突出衰老的一个迄今未被重视的方面，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对于成功的脑衰老可能很重要。