权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要对艾滋病毒携带者(PLWH)的脑组织以及艾滋病毒/艾滋病动物模型的研究表明淀粉样蛋白β(Aβ)的产生和聚集增加，淀粉样斑块，牛磺酸过度磷酸化增加 (Ptau)和形成神经原纤维缠结样结构。重要的是，这些老年痴呆症的存在 PLWH中的疾病(AD)样病理与神经变性增加和HIV相关神经认知障碍(手)。艾滋病病毒增加Aβ产生的机制病理，并诱导AD样中枢神经系统(CNS)损害尚不清楚。尽管大多数PLWH 世卫组织显示与手相关的中枢神经系统淀粉样斑块和ptau增加已长期存在抗逆转录病毒治疗(ART)，ART在Aβ和Ptau产生中的作用，以及AD样病理尚未得到调查过了。我们的体内和体外研究表明，HIV-1感染显著增加了中枢神经系统 Aβ42(Aβ的主要神经毒性成分)和ptau的水平，这与神经元损伤有关血脑屏障(BBB)损伤。值得注意的是，我们证明了CCR5拮抗剂马拉韦罗(MVC)，抑制艾滋病毒诱导的Aβ42和PTAU的产生，防止艾滋病毒诱导的神经元和血脑屏障的损伤，降低中枢神经系统病毒载量。因此，我们假设CCR5在形成过程中起主要作用 PLWH中淀粉样斑块和ptau病变的研究以及靶向CCR5预防艾滋病毒诱导的Aβ 产生，防止淀粉样斑块和ptau的形成，并消除神经元丢失，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，并进一步调查一种常用的抗逆转录病毒(ARV)药物(AZT)对HIV- 1诱导的淀粉样蛋白生成、ptau和中枢神经系统损伤(AIM-1)、神经炎症和Aβ清除(AIM-2)、淀粉样前体蛋白(APP)和牛磺酸(AIM-3)的代谢。这些机械研究将有助于确定艾滋病毒是否通过干扰i)Aβ的降解和清除，ii)APPα-分泌酶或β- 分泌途径；iii)与HIV诱导的ptau相关的效应器和途径，iv)ARV(AZT)的作用，以及v)CCR5是否调节这些效应。对这一R21应用的研究是非常有意义的美国国立卫生研究院高度重视的研究领域，重点是“研究艾滋病毒引起的病理生理机制” ART…患者的中枢神经系统功能障碍。和开发新的治疗方法来缓解中枢神经系统艾滋病毒感染的并发症。CCR5拮抗剂MVC是FDA批准的药物，我们的研究将确定微血管密度是否能阻止中枢神经系统Aβ的产生、淀粉样斑块和ptau的形成艾滋病毒感染与抗逆转录病毒治疗及其相关机制。结果将证明CCR5在艾滋病毒中的作用- 诱导中枢神经系统β和ptau的产生，为治疗靶向CCR5提供新途径预防HIV-1诱导的淀粉样变、ptau病理、神经元损伤和神经认知损伤。