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.

总结 全世界有超过3700万人感染艾滋病毒，多达50%的人受到某种形式的艾滋病的影响。 神经功能障碍尽管有效的抗逆转录病毒治疗（ART）延长了患有 艾滋病毒（PWH）、降低艾滋病毒相关神经认知障碍（HAND）和其他疾病患病率的治疗 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靶向机制 在病毒抑制的PWH中，特别是在老龄化人群中。事实上，有证据表明，老化的威尔斯亲王医院可能 易患与年龄有关的疾病，如阿尔茨海默病（AD）。在HIV感染早期，HIV感染者 单核细胞进入大脑并将感染传播给常驻的小胶质细胞，然后释放HIV，HIV蛋白， 炎性细胞因子，其刺激星形胶质细胞中的促炎表型。反应性星形胶质细胞是 这是HAND和AD死后脑组织的标志星形胶质细胞具有多种稳态功能， 可能会被慢性低水平的艾滋病毒感染，长期暴露于ART以及年龄和AD相关的 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产物的浓度， 底物（葡萄糖，乳酸盐和谷氨酰胺）可用于细胞外空间的神经元。尽管这一关键 功能，以维持生物能稳态的大脑和充分记录的证据，生物能 然而，在HAND和AD期间，关于这些过程如何在反应性星形胶质细胞中受到影响的知之甚少。我们 最近发现HIV和ART刺激星形胶质细胞从主要的糖酵解和分泌 副产品乳酸盐，依靠氧化磷酸化来满足能量需求。为了实现这一增长 在线粒体活动中，反应性星形胶质细胞增加线粒体生物发生因子TFAM的水平，TFAM是 与神经元中TFAM表达和活力的降低相关。重要的是，这种神经毒性被阻断 通过抑制线粒体活性和减少炎性表型的抗炎化合物， 星形胶质细胞。然而，在反应性星形胶质细胞中线粒体活性增加和细胞凋亡之间的机制联系， 神经元中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 通过检验年龄相关蛋白Aβ与HIV协同作用的假设， ART和炎性细胞因子以年龄和TFAM依赖性方式诱导反应性星形胶质细胞。 SA 1将在来自年轻和老年供体的人类星形胶质细胞培养物中测试TFAM敲除如何改变 反应性星形胶质细胞中线粒体活性和炎症基因表达。SA 2将进行尸检调查 来自HIV-、HIV-伴AD的脑组织以及PWH伴和不伴HAND的脑组织中星形胶质细胞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，以1）解决艾滋病毒- 相关的合并症;和2）推进基础和行为科学研究的交叉领域。