Extracellular vesicles in AD-like pathology in HIV and its potential therapeutics

HIV 中 AD 样病理学中的细胞外囊泡及其潜在治疗方法

• 批准号: 10618024
• 负责人: Tauheed Ishrat
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618024
• 关键词: Acceleration; Affect; Age; Aging; Alzheimer associated neurodegeneration; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-42; Animals; Anti-Retroviral Agents; Award; Biological Response Modifier Therapy; Blood - brain barrier anatomy; Brain; Bypass; Cells; Central Nervous System Diseases; Cessation of life; Cognitive; Curcumin; Data; Development; Drug toxicity; Early Onset Alzheimer Disease; Enzymes; Formulation; Goals; HIV; HIV Infections; HIV Seronegativity; Human; In Vitro; Induced pluripotent stem cell derived neurons; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Intranasal Administration; Life Expectancy; Macrophage; Measures; Mediating; Memory; Memory impairment; Microglia; Microtubule-Associated Proteins; Modeling; Mus; Nerve Degeneration; Neurocognition; Neurons; Oxidative Stress; Parkinson Disease; Pathogenesis; Pathway interactions; Penetration; Permeability; Persons; Pharmaceutical Preparations; Population; Premature aging syndrome; Principal Investigator; Proteins; Regimen; Reporting; Research; Research Personnel; Role; Route; Senile Plaques; Site; Symptoms; Synaptophysin; System; TXNIP gene; Testing; Therapeutic; Time; Toxic effect; Transgenic Organisms; Viral Proteins; Virus; aged; antioxidant enzyme; antiretroviral therapy; attenuation; blood-brain barrier crossing; brain cell; brain tissue; cytokine; efficacy evaluation; experience; extracellular vesicles; hyperphosphorylated tau; improved; in vitro Model; inhibitor; mouse model; nanocarrier; nanoformulation; neuroinflammation; neuron loss; novel; protein biomarkers; water maze

Studies of brain tissues from people living with HIV (PLWH) age from 38-60 years, showed increased amyloid plaques and tau hyperphosphorylation compared to age-matched HIV-negative subjects. PLWH who are on antiretroviral therapy (ART) live longer but experience neurodegenerative conditions related to HIV as they age. In 2018, 51% of PLWH in the U.S. were age 50 or older, and in the next 5-10 years, this population will be in their sixties, the prime age when Alzheimer’s disease (AD) symptoms begin to manifest. Further, premature aging with HIV infection is reported to affect neurocognition in PLWH. Since aging is a significant risk factor for AD development and HIV can cause premature aging, it's critically important to examine the relationship between HIV-induced aging and AD. Compared to age-matched HIV-negative subjects, studies of brain tissues from people living with HIV (PLWH) aged 38-60 showed increased amyloid plaques and tau hyperphosphorylation. However, the underlying mechanism by which HIV causes AD-associated neurodegeneration and memory impairment in PLWH is not well studied. Moreover, due to the inability of ARVs to cross the blood-brain barrier (BBB), the current ARV regimens are insufficient in suppressing HIV in the brain, which can further exacerbate neurodegenerative conditions in the aged HIV population. Our preliminary studies have shown that extracellular vesicles (EVs) derived from HIV-infected macrophages carry higher pro-inflammatory cytokines and low antioxidant enzymes. Further, exposure of these EVs from HIV-infected macrophages to SH-SY5Y neuronal cells caused increased toxicity, IL-1β levels, and neuronal loss (MAP2). We have also demonstrated that EVs administered by the intranasal route can bypass the BBB and be detected in the brain. Further, we showed that the elvitegravir (an antiretroviral drug) could be loaded into EVs and delivered across the BBB in an in vitro model. This proposal will elucidate the role of the HIV components packaged in EVs in causing AD-like pathology through the TXNIP inflammatory pathway. We will also use EVs as nanocarriers to improve curcumin (TXNIP inhibitor) and EVG levels across the BBB, thus effectively suppressing inflammation with minimal/tolerable drug toxicity.

对 38-60 岁艾滋病毒感染者 (PLWH) 脑组织的研究表明， 与年龄匹配的 HIV 阴性受试者相比，淀粉样斑块和 tau 蛋白过度磷酸化。感染者 接受抗逆转录病毒治疗 (ART) 的人寿命更长，但会经历与 HIV 相关的神经退行性疾病，例如 他们变老了。 2018 年，美国 51% 的 PLWH 年龄在 50 岁或以上，并且在未来 5-10 年里，这一人群 六十多岁时，正是阿尔茨海默病（AD）症状开始显现的黄金年龄。更远， 据报道，艾滋病毒感染引起的过早衰老会影响艾滋病病毒感染者的神经认知。由于衰老是一个重大风险 AD 发展的因素和 HIV 可能导致过早衰老，因此检查两者之间的关系至关重要 HIV 引起的衰老和 AD 之间的关系。 与年龄匹配的艾滋病毒阴性受试者相比，对艾滋病毒感染者脑组织的研究 38-60 岁的感染者 (PLWH) 表现出淀粉样斑块增加和 tau 蛋白过度磷酸化。然而，底层 HIV 导致 PLWH 中与 AD 相关的神经变性和记忆障碍的机制尚不明确 好好研究了。此外，由于抗逆转录病毒药物无法穿过血脑屏障（BBB），目前的抗逆转录病毒药物 治疗方案不足以抑制大脑中的艾滋病毒，这可能进一步加剧神经退行性疾病 艾滋病毒老年人口的状况。我们的初步研究表明，细胞外囊泡（EV） 源自感染艾滋病毒的巨噬细胞携带较高的促炎细胞因子和较低的抗氧化酶。 此外，将来自 HIV 感染巨噬细胞的这些 EV 暴露于 SH-SY5Y 神经元细胞会导致 毒性、IL-1β 水平和神经元损失 (MAP2)。我们还证明了电动汽车由 鼻内途径可以绕过血脑屏障并在大脑中被检测到。 此外，我们还表明，埃维特拉韦（一种抗逆转录病毒药物）可以装载到电动汽车中并输送 在体外模型中穿过血脑屏障。该提案将阐明包装中的艾滋病毒成分的作用 EV 通过 TXNIP 炎症途径引起 AD 样病理。我们还将使用电动汽车作为 纳米载体可提高姜黄素（TXNIP抑制剂）和EVG在BBB中的水平，从而有效抑制 炎症具有最小/可耐受的药物毒性。