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

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Alzheimer' 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

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 神经功能障碍。尽管有效的抗逆转录病毒疗法（ART）可以延长患有此病的人的寿命 HIV (PWH)、降低 HIV 相关神经认知障碍 (HAND) 患病率的治疗和其他 缺乏与年龄有关的疾病。反应性星形胶质细胞中线粒体活性的增加在 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 在病毒抑制的感染者中，特别是在老龄化人群中。事实上，有证据表明，老龄化的产妇可能会 容易患上与年龄相关的疾病，例如阿尔茨海默病（AD）。 HIV感染早期，HIV感染者 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。反应性星形胶质细胞是 HAND 和 AD 死后脑组织的标志。星形胶质细胞具有许多稳态功能， 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 β 淀粉样蛋白 (Ab)。星形胶质细胞的一项重要功能是缓冲代谢物的浓度 细胞外空间神经元可利用的底物（葡萄糖、乳酸和谷氨酰胺）。尽管这至关重要 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，但人们对这些过程如何在反应性星形胶质细胞中受到影响知之甚少。我们已经 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，依靠氧化磷酸化来满足能量需求。为了实现这一增长 在线粒体活性中，反应性星形胶质细胞增加线粒体生物发生因子 TFAM 的水平，该因子 与神经元中 TFAM 表达和活力的减少有关。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 星形胶质细胞。然而，反应性星形胶质细胞线粒体活性增加与 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。 SA2将进行事后调查 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 与 Ab 斑块的关系。这些目标针对艾滋病研究优先事项办公室：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研究领域。