Aging, Brain Cytokines and HIV-Associated Dementia

衰老、脑细胞因子和 HIV 相关痴呆

• 批准号: 6697401
• 负责人: Rodney W Johnson
• 金额: $ 34.04万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697401
• 关键词: AIDS /HIV neuropathy; Alzheimer's disease; HIV envelope protein gp120; age difference; aging; antioxidants; behavior test; catheterization; cytokine; dementia; free radical oxygen; laboratory mouse; learning; mature animal; memory; microglia; microinjections; neurophysiology; neuropsychological tests; neuropsychology; oxidative stress; pathologic process; psychological aspect of aging; psychomotor function; tissue /cell culture

DESCRIPTION (provided by applicant): The inflammatory cytokine interleukin-6 (IL-6) is increasingly expressed in the brain of aged mice. The heightened expression is due to increased binding of nuclear factor kappa B to the IL-6 gene promoter in microglial cells, which is triggered by an age-associated increase in oxidative stress. The chronic over expression of IL-6 as well as other inflammatory cytokines in the brains of older adults is thought to play a role in age-related changes in cognitive function and behavior and may predispose individuals to the onset of Alzheimer's disease. This is important for HIV-infected patients who now live longer due to the success of HAART therapy because the development of HIV-associated dementia (HAD) appears to involve the same cast of characters that are affected by normal aging. Therefore, the goal of this proposal is to investigate if neurocognitive complications associated with HIV disease are exacerbated by other neurophysiologic changes that occur during "normal" aging. We propose three specific aims in an aged mouse model to address this issue. In the first aim, learning, memory, and motor skills in adult and aged mice will be assessed and oxidative stress and several inflammatory cytokines will be measured in the brain. Adult and aged mice will be treated with HIV-1 gp120 centrally via an indwelling intracerebroventricular (ICV) cannula to determine if aging might exacerbate oxidative stress and production of inflammatory cytokines in the brain of older adults with HIV disease. In the second aim we will compare learning, memory, and motor skills of adult and aged mice injected ICV with HIV-1 gpl20 or cytokines that are secreted by gpl20- stimulated microglia. Finally in the third aim we will reduce oxidative stress and inflammatory cytokines in the brain of aged mice to determine if this reduces the age-associated exacerbation of neurobehavioral deficits caused by HIV-1 gp 120 in the brain. We contend that this model using ICV injections of HIV-1 gpl20 and inflammatory cytokines is critically needed to understand not only the effects of aging on the neurocognitive complications associated with HIV disease, but also to provide insights into the interaction between HIV-induced pathophysiologies and Alzheimer's disease-related pathophysiologies that may be occurring. We have developed all of the techniques to successfully complete these objectives. This proposal addresses a critically important but as yet relatively unexplored area by carefully investigating how aging and HIV-1 gp120 interact in the brain to affect behavior.

描述（由申请人提供）：炎症细胞因子白细胞介素-6（IL-6）在老年小鼠的大脑中表达越来越多。表达升高是由于小胶质细胞中核因子 kappa B 与 IL-6 基因启动子的结合增加，这是由年龄相关的氧化应激增加引发的。老年人大脑中 IL-6 以及其他炎症细胞因子的长期过度表达被认为在认知功能和行为的年龄相关变化中发挥着作用，并可能使个体易患阿尔茨海默氏病。这对于 HIV 感染者来说非常重要，由于 HAART 治疗的成功，他们现在的寿命更长了，因为 HIV 相关痴呆 (HAD) 的发展似乎与受正常衰老影响的特征相同。因此，该提案的目的是调查与艾滋病毒相关的神经认知并发症是否会因“正常”衰老过程中发生的其他神经生理变化而加剧。我们在老年小鼠模型中提出了三个具体目标来解决这个问题。第一个目标是评估成年和老年小鼠的学习、记忆和运动技能，并测量大脑中的氧化应激和几种炎症细胞因子。成年和老年小鼠将通过留置脑室内 (ICV) 插管接受 HIV-1 gp120 集中治疗，以确定衰老是否会加剧患有 HIV 疾病的老年人大脑中的氧化应激和炎症细胞因子的产生。在第二个目标中，我们将比较 ICV 注射 HIV-1 gpl20 或 gpl20 刺激的小胶质细胞分泌的细胞因子的成年和老年小鼠的学习、记忆和运动技能。最后，在第三个目标中，我们将减少老年小鼠大脑中的氧化应激和炎症细胞因子，以确定这是否可以减少大脑中由 HIV-1 gp 120 引起的与年龄相关的神经行为缺陷恶化。我们认为，迫切需要这种使用 ICV 注射 HIV-1 gpl20 和炎症细胞因子的模型，不仅可以了解衰老对与 HIV 疾病相关的神经认知并发症的影响，而且还可以深入了解 HIV 诱导的病理生理学和炎症之间的相互作用。可能正在发生的与阿尔茨海默病相关的病理生理学。我们已经开发了成功完成这些目标的所有技术。该提案通过仔细研究衰老和 HIV-1 gp120 如何在大脑中相互作用以影响行为，解决了一个至关重要但相对尚未探索的领域。