Aging, Brain Cytokines and HIV-Associated Dementia

描述（由申请人提供）：炎症细胞因子白细胞介素-6（IL-6）在老年小鼠的脑中表达增加。表达增加是由于核因子κ B与小胶质细胞中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触发的。IL-6以及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认知功能和行为的年龄相关变化中起作用，并且可能使个体易于发生阿尔茨海默病。这对于由于HAART治疗的成功而活得更长的HIV感染患者来说很重要，因为HIV相关性痴呆（HAD）的发展似乎涉及受正常衰老影响的相同角色。因此，本提案的目标是调查与HIV疾病相关的神经认知并发症是否会因“正常”衰老期间发生的其他神经生理学变化而加剧。我们提出了三个具体的目标，在老年小鼠模型来解决这个问题。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的脑室内（ICV）插管用HIV-1 gp 120集中治疗，以确定衰老是否可能加剧患有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，我们将比较用HIV-1 gp 120或由gp 120刺激的小胶质细胞分泌的细胞因子ICV注射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性细胞因子，以确定这是否减少了大脑中由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，使用ICV注射HIV-1 gp 120和炎性细胞因子的这种模型是非常需要的，不仅要了解衰老对与HIV疾病相关的神经认知并发症的影响，而且要深入了解HIV诱导的病理生理学和可能发生的阿尔茨海默病相关的病理生理学之间的相互作用。我们已经开发了所有的技术来成功地完成这些目标。这项提案通过仔细研究衰老和HIV-1 gp 120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.