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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.

摘要对艾滋病毒感染者（PLWH）的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）生成和聚集增加，淀粉样蛋白斑块，Tau过度磷酸化增加（pTau）和神经元缠结样结构的形成。重要的是，这些老年痴呆症的存在 PLWH中的疾病（AD）样病理与神经变性和HIV相关性增加有关。神经认知障碍（HAND）。HIV增加Aβ产生的机制，pTau 病理学，并诱导AD样中枢神经系统（CNS）损伤是未知的。尽管大多数艾滋病毒携带者显示与HAND相关的CNS淀粉样蛋白斑块和pTau增加的患者，抗逆转录病毒疗法（ART），ART在Aβ和pTau产生中的作用，以及AD样病理学尚未被研究。研究了我们的体内和体外研究表明，HIV-1感染显著增加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CCR 5拮抗剂马拉韦罗（MVC），消除HIV诱导的Aβ42和pTau的产生，防止HIV诱导的神经元和BBB损伤，降低CNS病毒载量。因此，我们假设CCR 5在形成中起主要作用。 PLWH中淀粉样蛋白斑块和pTau病理学以及靶向CCR 5可预防HIV诱导的Aβ 产生，防止淀粉样蛋白斑和pTau的形成，并消除神经元损失，和手在这些探索性研究中，我们将使用经验证的HIV/AIDS动物模型来检验这一假设，进一步研究一种常用的抗逆转录病毒（ARV）药物（叠氮胸苷[AZT]）对艾滋病毒的影响， 1-诱导淀粉样蛋白生成、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。这些机械研究将有助于确定 HIV是否通过干扰i）Aβ降解和清除，ii）APP α-分泌酶或β- 分泌酶途径; iii）与HIV诱导的pTau相关的效应物和途径，iv）ARV（AZT）的作用，和v）CCR 5是否调节这些作用。在R21应用方面的研究非常重要， NIH的高优先级研究领域，重点是“检查艾滋病毒诱导的中枢神经系统功能障碍在艺术设置.和开发新的治疗方法，以减轻CNS 艾滋病毒感染的并发症”。CCR 5拮抗剂MVC是FDA批准的药物，我们的研究将确定MVC是否在以下情况下防止CNS Aβ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CCR 5在HIV中的作用- 诱导CNS中Aβ和pTau的产生，并为治疗靶向CCR 5提供新的方法预防HIV-1诱导的淀粉样蛋白生成、pTau病理学、神经元损伤和神经认知障碍。