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 全球超过3700万人感染了艾滋病毒，多达50％的人受某种形式的影响 神经功能障碍。尽管有效抗逆转录病毒疗法（ART）延长了 艾滋病毒（PWH），降低与艾滋病毒相关神经认知障碍（手）和其他其他患病率的治疗方法 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 神经元中的线粒体功能障碍，这可能是神经元功能障碍的基础机制 在病毒抑制的PWH中，尤其是在衰老人群中。确实，有证据表明PWH衰老可能是 容易受到与年龄有关的疾病（例如阿尔茨海默氏病）（AD）。在艾滋病毒感染期间，感染了艾滋病毒 单核细胞进入大脑并将感染传播给居民小胶质细胞，然后释放HIV，HIV蛋白和 炎性细胞因子，刺激星形胶质细胞中促炎的表型。反应性星形胶质细胞是 手工和AD的验尸后脑组织的标志。 Astroglia具有许多稳态功能， 慢性低级HIV感染，长期暴露于ART以及与年龄和广告有关的可能会破坏 蛋白质β淀粉样蛋白（AB）。星形胶质细胞的一个重要功能是缓冲代谢的浓度 细胞外空间中可用于神经元的底物（葡萄糖，葡萄糖和谷氨酰胺）。尽管至关重要 在大脑中保持生物能稳态的功能和有据可查的生物能证据 在手和AD期间的缺陷，对这些过程在反应性星形胶质体中如何影响这些过程知之甚少。我们已经 最近发现，艾滋病毒和艺术刺激了星形胶质细胞的转换，使其成为主要的糖酵解和分泌 副产品乳酸，依靠氧化磷酸化来满足能量需求。实现这一增加 在线粒体活性中，反应性星形胶质细胞增加线粒体生物发生因子TFAM的水平，即 与神经元中TFAM表达和生存能力的降低有关。重要的是，这种神经毒性被阻止 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中线粒体活性的增加与 尚不清楚神经元中线粒体生物发生的降低。我们将研究星形胶质的作用 通过测试与年龄相关蛋白Aβ与HIV协同作用的假设，通过测试衰老PWH的代谢。 艺术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将在年轻和老年捐助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将在验尸中进行调查 来自AD的HIV-，HIV-的脑组织，在PWH中具有和没有手动变化的Astroglial TFAM和 与AB斑块的关系。这些目的是向艾滋病研究重点介绍1）解决HIV- 相关的合并症；和2）提前基础科学和行为科学研究的横切领域。