Astoglial reactivity and metabolism in aging people with HIV

老年艾滋病毒感染者的星形胶质细胞反应性和代谢

基本信息

批准号：
10846438
负责人：
Jerel Adam Fields
金额：
$ 31.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10846438
关键词：
Abeta clearance Acquired Immunodeficiency Syndrome Address Adherence Administrative Supplement Affect Age Age Factors Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease diagnosis Alzheimer&apos s disease risk Alzheimer&apos s neuropathogenesis Amyloid beta-42 Amyloid beta-Protein Anti-Inflammatory Agents Area Astrocytes Autopsy Basic Science Behavioral Behavioral Sciences Bioenergetics Biogenesis Biological Brain Buffers Chronic Cognitive Deposition Diagnosis Diffuse Disease Early identification Elderly Exposure to Extracellular Space Gene Expression Genetic Glucose Glutamine HIV HIV Infections HIV-associated neurocognitive disorder Homeostasis Human Human immunodeficiency virus test In Vitro Infection Inflammation Inflammatory Investigation Letters Link Longevity Memory impairment Metabolic Metabolism Microglia Mitochondria Nerve Degeneration Neurodegenerative Disorders Neurologic Dysfunctions Neuronal Dysfunction Neurons Neuropathogenesis Oxidative Phosphorylation Pathology Persons Phenotype Play Population Predisposition Prevalence Process Proteins Reporting Research Research Priority Risk Rodent Rodent Model Role Senile Plaques Severities Stimulus Testing Therapeutic Viral abeta accumulation age related age related neurodegeneration aged amnestic mild cognitive impairment antiretroviral therapy brain parenchyma brain tissue cognitive performance comorbidity cytokine frontal lobe high risk improved intraneuronal beta amyloid knock-down mitochondrial dysfunction monocyte neurotoxicity novel therapeutic intervention parent grant prevent response spatial relationship synergism transcription factor transcriptome sequencing

项目摘要

SUMMARY Over 37 million people worldwide are infected with HIV and as many as 50% are affected by some form of neurological dysfunction. Despite effective antiretroviral therapy (ART) extending the lifespans of people with HIV (PWH), treatments to reduce the prevalence of HIV-associated neurocognitive disorder (HAND) and other age-related diseases are lacking. Increased mitochondrial activity in reactive astroglia play a causal role in mitochondrial dysfunction in neurons and this may be a targetable mechanism underlying neuronal dysfunction in virally suppressed PWH, particularly in aging populations. Indeed, there is evidence that aging PWH may be susceptible to age-related diseases such as Alzheimer’s disease (AD). Early during HIV infection, HIV-infected monocytes enter the brain and spread infection to resident microglia that then release HIV, HIV proteins, and inflammatory cytokines, which stimulate a proinflammatory phenotype in astroglia. Reactive astroglia are a hallmark of postmortem brain tissues from HAND and AD. Astroglia have many homeostatic functions, which are likely disrupted by chronic low-level HIV infection, long-term exposure to ART and the age- and AD-related protein beta amyloid (Ab). One important function of astroglia is to buffer the concentrations of metabolic substrates (glucose, lactate, and glutamine) available to neurons in the extracellular space. Despite this crucial function to maintain bioenergetic homeostasis in the brain and the well-documented evidence of bioenergetic deficits during HAND and AD, little is known about how these processes are affected in reactive astroglia. We’ve recently discovered that HIV and ART stimulate a switch in astroglia from being primarily glycolytic and secreting the byproduct lactate, to relying on oxidative phosphorylation to meet energy demands. To achieve this increase in mitochondrial activity, reactive astroglia increase levels of the mitochondrial biogenesis factor TFAM, which is associated with a reduction in TFAM expression and viability in neurons. Importantly, this neurotoxicity is blocked by anti-inflammatory compounds that inhibit mitochondrial activity and reduce the inflammatory phenotype of astroglia. However, the mechanistic link between increased mitochondrial activity in reactive astroglia and the reduction in mitochondrial biogenesis in neurons is not understood. We will investigate the role of astroglial metabolism in aging PWH by testing the hypothesis that the age-related protein Aβ synergizes with HIV, ART and inflammatory cytokines in an age- and TFAM-dependent manner to induce reactive astroglia. SA1 will test in human astrocyte cultures from young and aged donors how TFAM knockdown alters mitochondrial activity and inflammatory gene expression in reactive astroglia. SA2 will investigate in postmortem brain tissues from HIV-, HIV- with AD, and in PWH with and without HAND changes in astroglial TFAM and the relationship with Ab plaques. These AIMs address the Office of AIDS Research Priorities to 1) Address HIV- Associated Comorbidities; and 2) Advance Cross-Cutting Areas of research in the basic and behavioral sciences.

概括全球有超过 3700 万人感染艾滋病毒，其中多达 50% 的人受到某种形式的影响尽管有效的抗逆转录病毒治疗（ART）可以延长患者的寿命。 HIV (PWH)、降低 HIV 相关神经认知障碍 (HAND) 患病率的治疗和其他缺乏与年龄相关的疾病，反应性星形胶质细胞中线粒体活性的增加起着因果作用。神经元线粒体功能障碍，这可能是神经元功能障碍的潜在机制在病毒抑制的 PWH 中，特别是在老龄化人群中，确实有证据表明老龄化的 PWH 可能会受到影响。容易患上与年龄相关的疾病，例如阿尔茨海默氏病（AD）。单核细胞进入大脑并将感染传播到驻留的小胶质细胞，然后释放 HIV、HIV 蛋白和炎症细胞因子，刺激星形胶质细胞的促炎表型，是一种反应性星形胶质细胞。 HAND 和 AD 死后脑组织的标志是具有许多稳态功能。可能会受到慢性低水平 HIV 感染、长期接触 ART 以及与年龄和 AD 相关的疾病的干扰星形胶质细胞的一项重要功能是缓冲代谢浓度。尽管这一点至关重要，但细胞外空间中的神经元可利用的底物（葡萄糖、乳酸和谷氨酰胺）。维持大脑生物能稳态的功能以及生物能的有据可查的证据尽管 HAND 和 AD 期间存在缺陷，但我们对反应性星形胶质细胞如何影响这些过程知之甚少。最近发现 HIV 和 ART 刺激星形胶质细胞从主要糖酵解和分泌转变副产物乳酸，要依靠氧化磷酸化来满足能量需求来实现这种增加。在线粒体活性中，反应性星形胶质细胞增加线粒体生物合成因子 TFAM 的水平，该因子与神经元中 TFAM 表达和活力的减少相关，重要的是，这种神经毒性被阻断。通过抑制线粒体活性并减少炎症表型的抗炎化合物然而，反应性星形胶质细胞线粒体活性增加与星形胶质细胞之间的机制联系。神经元线粒体生物发生的减少尚不清楚，我们将研究星形胶质细胞的作用。通过测试年龄相关蛋白 Aβ 与 HIV 协同作用的假设，研究衰老 PWH 中的代谢， ART 和炎症细胞因子以年龄和 TFAM 依赖性方式诱导反应性星形胶质细胞。 SA1 将在年轻和老年捐赠者的人类星形胶质细胞培养物中测试 TFAM 敲低如何改变反应性星形胶质细胞中的线粒体活性和炎症基因表达将在死后进行研究。来自 HIV 感染、HIV 感染 AD 以及 PWH 患者的脑组织，无论是否存在 HAND 变化，星形胶质细胞 TFAM 和这些目标解决了艾滋病研究办公室的优先事项：1) 解决艾滋病毒- 相关合并症；2) 推进基础科学和行为科学的交叉领域研究。