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Preventing Alzheimer's Disease Like Brain Pathology in HIV Infection by Targeting CCR5

通过靶向 CCR5 预防阿尔茨海默病，例如 HIV 感染中的脑病理学

基本信息

批准号：
10301369
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 22.98万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2022-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301369
关键词：
70-kDa Ribosomal Protein S6 Kinases AIDS/HIV problem Abeta clearance Abeta synthesis Acids Address Alzheimer like pathology Alzheimer&apos s Disease Amino Acids Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Anti-Retroviral Agents Area Attention Autopsy Blood - brain barrier anatomy Brain Brain Pathology C-terminal CCL3 gene CCL4 gene CCR5 gene CDK5 gene Cell Line Cells Cognitive Complex Cyclic AMP-Dependent Protein Kinases Development Enzymes FDA approved Functional disorder Gliosis HIV HIV Infections HIV-1 Hippocampus (Brain)Human Impairment In Vitro Individual Infection Inflammatory Injury Interleukin-6 Lesion Leukocytes Mediating Metabolism Mus Neprilysin Nerve Degeneration Neuraxis Neurocognitive Deficit Neurofibrillary Tangles Neuronal Injury Neurons Pathology Pathway interactions Persons Phagocytosis Pharmaceutical Preparations Phosphorylation Phosphotransferases Plasma Play Production Proto-Oncogene Proteins c-akt RANTES RNA Research Priority Role Senile Plaques Speed Structure Testing Therapeutic Tissue Sample United States National Institutes of Health Viral Load result Viral Proteins Zidovudine alpha secretase amyloid formation amyloid precursor protein processing amyloidogenesis antagonist antiretroviral therapy beta secretase brain tissue central nervous system injury design in vivo information processing mouse model neurofibrillary tangle formation neuroinflammation neuron loss neurotoxic novel novel therapeutic intervention prevent protein metabolism public health relevance putamen secretase tau Proteins tau-1 therapeutic target upstream kinase vascular injury

项目摘要

ABSTRACT Studies of brain tissues from people living with HIV (PLWH), as well as HIV/AIDS animal models, showed increased amyloid-β (Aβ) production and aggregation, amyloid plaques, increased Tau hyperphosphorylation (pTau) and formation of neurofibrillary tangles-like structures. Importantly, the presence of these Alzheimer’s Disease (AD)-like pathologies in PLWH is associated with increased neurodegeneration and HIV-associated neurocognitive impairment (HAND). The mechanisms through which HIV increase Aβ production, pTau pathologies, and induce AD-like central nervous system (CNS) impairment are not known. Although most PLWH who showed increased CNS amyloid plaques and pTau associated with HAND had been on long-term antiretroviral therapy (ART), the role of ART in Aβ and pTau production, and AD-like pathologies has not been investigated. Our in-vivo and ex-vivo studies demonstrated that HIV-1 infection significantly increased CNS levels of Aβ42 (the major neurotoxic component of Aβ) and pTau, and this was associated with neuronal damage and blood-brain barrier (BBB) injury. Significantly, we demonstrated that the CCR5 antagonist, maraviroc (MVC), abrogated HIV-induced production of Aβ42 and pTau, prevented HIV-induced damage to neurons and the BBB, and decreased CNS viral loads. Therefore, we hypothesize that CCR5 plays a major role in the formation of amyloid plaques and pTau pathology in PLWH and that targeting CCR5 prevents HIV-induced Aβ production, prevents the formation of amyloid plaques and pTau, and abrogates neuronal loss, and HAND. In these exploratory studies, we will use a validated HIV/AIDS animal model to test this hypothesis and further investigate the effects of a commonly prescribed antiretroviral (ARV) drug (azidothymidine [AZT]) on HIV- 1-induced amyloidogenesis, pTau and CNS injury (Aim-1), neuroinflammation and Aβ clearance (Aim-2), the metabolism of amyloid precursor proteins (APP) and Tau (Aim-3). These mechanistic studies will help determine whether HIV induce Aβ production by interfering with i) Aβ degradation and clearance, ii) APP α-secretase or β- secretase pathways; iii) the effectors and pathways associated with HIV-induce pTau, iv) the role of ARV (AZT), and v) whether CCR5 modulates these effects. Studies in this R21 application are very significant and address the NIH high priority research areas that focus on “Examining the pathophysiologic mechanisms of HIV-induced CNS dysfunction in the setting of ART…. and development of novel therapeutic approaches to mitigate CNS complications of HIV infection.” The CCR5 antagonist MVC is an FDA-approved drug and our study will determine whether MVC prevents CNS Aβ production, formation of amyloid plaques and pTau in the setting of HIV-infection and ART, and the associated mechanisms. The results will demonstrate the role of CCR5 in HIV- induced production of Aβ and pTau in the CNS and provide new approaches for therapeutically targeting CCR5 to prevent HIV-1-induced amyloidogenesis, pTau pathology, neuronal injury, and neurocognitive impairments.

抽象的对艾滋病毒感染者（PLWH）脑组织以及艾滋病毒/艾滋病动物模型的研究表明 β-淀粉样蛋白 (Aβ) 产生和聚集增加、淀粉样斑块、Tau 过度磷酸化增加 (pTau) 和神经原纤维缠结样结构的形成。重要的是，这些阿尔茨海默病的存在 PLWH 中的疾病 (AD) 样病理与神经变性和 HIV 相关的增加有关神经认知障碍（HAND）。 HIV 增加 Aβ 产生、pTau 的机制病理学以及引起 AD 样中枢神经系统 (CNS) 损伤的情况尚不清楚。尽管大多数感染者长期服用与 HAND 相关的中枢神经系统淀粉样蛋白斑块和 pTau 蛋白增加的患者抗逆转录病毒治疗 (ART)、ART 在 Aβ 和 pTau 产生中的作用以及 AD 样病理尚未得到证实调查了。我们的体内和离体研究表明，HIV-1 感染显着增加中枢神经系统 (CNS) Aβ42（Aβ 的主要神经毒性成分）和 pTau 水平，这与神经元损伤有关和血脑屏障（BBB）损伤。值得注意的是，我们证明了 CCR5 拮抗剂马拉韦罗 (MVC) 消除 HIV 诱导的 Aβ42 和 pTau 生成，防止 HIV 诱导的神经元和血脑屏障损伤，并减少中枢神经系统病毒载量。因此，我们假设CCR5在形成中起主要作用。 PLWH 中淀粉样斑块和 pTau 病理学的研究以及靶向 CCR5 可预防 HIV 诱导的 Aβ 产生，防止淀粉样斑块和 pTau 的形成，并消除神经元损失，以及手。在这些探索性研究中，我们将使用经过验证的艾滋病毒/艾滋病动物模型来检验这一假设并进一步研究常用抗逆转录病毒 (ARV) 药物（叠氮胸苷 [AZT]）对 HIV 的影响 1 诱导的淀粉样蛋白生成、pTau 和 CNS 损伤 (Aim-1)、神经炎症和 Aβ 清除 (Aim-2)、淀粉样前体蛋白 (APP) 和 Tau (Aim-3) 的代谢。这些机制研究将有助于确定 HIV 是否通过干扰 i) Aβ 降解和清除，ii) APP α-分泌酶或 β- 来诱导 Aβ 产生分泌酶途径； iii) 与 HIV 诱导 pTau 相关的效应器和途径，iv) 抗逆转录病毒药物 (AZT) 的作用， v) CCR5 是否调节这些效应。 R21 应用的研究非常重要，并且解决了 NIH 的高度优先研究领域专注于“检查 HIV 诱发的病理生理机制” ART 环境中的中枢神经系统功能障碍……和开发减轻中枢神经系统疾病的新治疗方法 HIV感染的并发症。” CCR5 拮抗剂 MVC 是 FDA 批准的药物，我们的研究将确定 MVC 是否会阻止中枢神经系统 Aβ 的产生、淀粉样斑块和 pTau 的形成 HIV 感染和 ART 以及相关机制。结果将证明 CCR5 在 HIV 中的作用诱导中枢神经系统中 Aβ 和 pTau 的产生，并为靶向 CCR5 的治疗提供新方法预防 HIV-1 诱导的淀粉样蛋白生成、pTau 病理、神经元损伤和神经认知障碍。