Aging, Brain Cytokines and HIV-Associated Dementia

描述(申请人提供)：炎症细胞因子白介素6(IL-6)在老年小鼠的大脑中表达增加。这种高表达是由于小胶质细胞中核因子kappa B与IL-6基因启动子结合增加，这是由年龄相关的氧化应激增加触发的。IL-6和其他炎性细胞因子在老年人大脑中的慢性过度表达被认为在与年龄相关的认知功能和行为变化中发挥作用，并可能使个人更容易发生阿尔茨海默病。这对艾滋病毒感染患者来说很重要，由于HAART治疗的成功，他们现在活得更长了，因为艾滋病毒相关痴呆(HAD)的发展似乎涉及到受正常衰老影响的相同角色。因此，这项建议的目标是调查与HIV疾病相关的神经认知并发症是否会因在“正常”衰老过程中发生的其他神经生理学变化而加剧。我们在一个老龄小鼠模型中提出了三个具体的目标来解决这个问题。在第一个目标中，将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性细胞因子。成年和老年小鼠将通过留置脑室(ICV)插管对HIV-1 gp120进行中央治疗，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性细胞因子的产生。在第二个目标中，我们将比较成年和老年小鼠的学习、记忆和运动技能，其中ICV注射了HIV-1gp20或gp20刺激的小胶质细胞分泌的细胞因子。最后，在第三个目标中，我们将减少老龄小鼠大脑中的氧化应激和炎性细胞因子，以确定这是否减少了大脑中HIV-1GP 120引起的与年龄相关的神经行为缺陷的恶化。我们认为，这种使用脑室注射HIV-1gp20和炎症细胞因子的模型是至关重要的，不仅是为了了解衰老对与HIV疾病相关的神经认知并发症的影响，而且也是为了深入了解HIV诱导的病理生理学和可能发生的阿尔茨海默病相关病理生理之间的相互作用。我们已经开发了成功完成这些目标的所有技术。这项建议通过仔细研究衰老和HIV-1 gp120在大脑中如何相互作用来影响行为，解决了一个极其重要但相对尚未探索的领域。

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.