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）：炎性细胞因子白细胞介素6（IL-6）在老年小鼠的大脑中越来越表达。表达的增强是由于核因子Kappa B与小胶质细胞中IL-6基因启动子的结合增加所致，这是由氧化应激与年龄相关的增加引起的。人们认为，老年人大脑中IL-6以及其他炎症细胞因子的慢性表达被认为在与年龄相关的认知功能和行为的变化中起作用，并且可能使个体倾向于阿尔茨海默氏病的发作。这对于因HAART治疗成功而寿命更长的艾滋病毒感染患者很重要，因为与艾滋病毒相关的痴呆症的发展（hot）似乎涉及受正常衰老影响的特征。因此，该提案的目的是研究是否因“正常”衰老期间发生的其他神经生理学变化加剧了与HIV疾病相关的神经认知并发症。我们在老年鼠标模型中提出了三个特定目标来解决此问题。在第一个目标中，将评估成人和老年小鼠的学习，记忆和运动技能，并将在大脑中测量几种炎症性细胞因子。成年小鼠和老年小鼠将通过HIV-1 GP120通过留置室内（ICV）插管中心地进行中心治疗，以确定衰老是否会加剧HIV疾病的大脑中衰老的氧化应激和炎性细胞因子的产生。在第二个目标中，我们将比较成人和老年小鼠的学习，记忆和运动技能，并向ICV注入HIV-1 GPL20或由GPL20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与大脑中HIV-1 GP 120引起的与年龄相关的神经行为缺陷的加重。我们争辩说，这种模型非常需要使用ICV注射HIV-1 GPL20和炎症细胞因子，这不仅需要了解衰老对与HIV疾病相关的神经认知并发症的影响，还可以洞悉HIV诱导的病理生理学和阿尔茨海默氏病的病理学的相互作用。我们已经开发了所有技术来成功完成这些目标。该提案通过仔细研究衰老和HIV-1 GP120在大脑中如何相互作用以影响行为，解决了至关重要的，但相对尚未探索的区域。