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

通过靶向 CCR5 预防阿尔茨海默氏病，例如 HIV 感染中的脑病理学

基本信息

批准号：
10161318
负责人：
GEORGETTE D. KANMOGNE
金额：
$ 19.13万
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/10161318
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 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 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.

抽象的研究了艾滋病毒（PLWH）患者的脑组织以及艾滋病毒/艾滋病动物模型的研究淀粉样蛋白-β（Aβ）的产生和聚集增加，淀粉样斑块，tau高磷酸化增加（PTAU）和神经纤维缠结的结构的形成。重要的是，这些阿尔茨海默氏症的存在 PLWH中的疾病（AD）类似病变与神经变性增加和与HIV相关的疾病有关神经认知障碍（手）。 HIV增加Aβ产生PTAU的机制病理和诱导类似AD的中枢神经系统（CNS）损害尚不清楚。虽然大多数PLWH 谁显示CNS淀粉样蛋白斑块和与手相关的PTAU长期存在抗逆转录病毒疗法（ART），ART在Aβ和PTAU产生中的作用，以及类似AD的病理学调查。我们的体内和前体内研究表明，HIV-1感染显着增加了CNS Aβ42的水平（Aβ的主要神经毒性成分）和PTAU，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Maroviroc（MVC），急救的HIV诱导的Aβ42和PTAU产生，防止了HIV诱导的神经元和BBB的损害并改善了CNS病毒载荷。因此，我们假设CCR5在形成中起着重要作用 PLWH中的淀粉样斑块和PTAU病理学的斑块和靶向CCR5可防止HIV诱导的Aβ 生产，防止形成淀粉样蛋白斑块和PTAU，并消除神经元损失，并手。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和进一步研究了常规规定的抗逆转录病毒（ARV）药物（氮杂酪氨酸[AZT]）对HIV-的影响 1诱导的淀粉样生成，PTAU和CNS损伤（AIM-1），神经炎症和Aβ清除率（AIM-2），淀粉样蛋白前体蛋白（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降解和清除诱导Aβ产生，ii）APPα-分泌酶还是β- 泌尿道途径； iii）与HIV诱导的PTAU相关的效果和途径，iv）ARV（AZT）的作用， v）CCR5是否调节这些效果。在此R21应用中的研究非常重要，并解决 NIH高优先研究领域，重点是“检查艾滋病毒诱导的病理生理机制 CNS功能障碍在艺术环境中……。并开发新的治疗方法来减轻CNS CCR5拮抗剂MVC是FDA批准的药物，我们的研究将确定MVC是否可以防止CNSAβ产生，在 HIV感染和艺术以及相关机制。结果将证明CCR5在HIV中的作用 CNS中诱导Aβ和PTAU的产生，并提供了针对CCR5治疗的新方法为了防止HIV-1诱导的淀粉样生成，PTAU病理学，神经元损伤和神经认知障碍。