Effects of opiates on neurons and their impact on HIV neuropathology

阿片类药物对神经元的影响及其对 HIV 神经病理学的影响

• 批准号: 10528436
• 负责人: Olimpia Meucci
• 金额: $ 41.72万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528436
• 关键词: Abeta synthesis; Acceleration; Affect; Aging; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Anti-Retroviral Agents; Area; Brain; Brain region; CXCR4 gene; Cells; Chronic; Cognitive deficits; Critical Pathways; Dendritic Spines; Development; Disease; Disease model; Endosomes; Engineering; Ethics; Evaluation; Experimental Models; Exposure to; Ferritin; Funding; Goals; HIV; HIV Envelope Protein gp120; HIV-associated neurocognitive disorder; Hippocampus; Homeostasis; Human; Impaired cognition; In Vitro; Inflammation; Inhibitory Synapse; Iron; Iron Chelation; Iron-Binding Proteins; Learning; Life Style; Macaca; Maintenance; Measurement; Measures; Mediating; Mediator; Membrane Microdomains; Memory; Modeling; Molecular; Monitor; Morphine; Morphology; Neurons; Neurotoxins; Opioid; Pathway interactions; Patients; Performance; Prefrontal Cortex; Property; Protein Family; Proteins; Proteolysis; Rattus; Recording of previous events; Recovery; Regulation; Research; Rodent; Rodent Model; Role; SIV; Signal Transduction; Simplexvirus; Stromal Cell-Derived Factor 1; Structure; Substance abuse problem; Synapses; Testing; Therapeutic; Tissues; Up-Regulation; Vertebral column; Viral; Viral Proteins; abeta oligomer; amyloid precursor protein processing; amyloidogenesis; anti aging; beta secretase; brain tissue; chemokine; cognitive performance; cognitive task; comorbidity; density; excitotoxicity; in vivo; inhibitor; iron metabolism; memory process; neuronal transport; neuropathology; neurotoxic; neurotransmission; novel; opioid abuse; opioid use; preservation; prevent; protein degradation; protein expression; secretase; synergism; tool; Abeta synthesis; Acceleration; Affect; Aging; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Animal Model; Animals; Anti-Retroviral Agents; Area; Brain; Brain region; CXCR4 gene; Cells; Chronic; Cognitive deficits; Critical Pathways; Dendritic Spines; Development; Disease; Disease model; Endosomes; Engineering; Ethics; Evaluation; Experimental Models; Exposure to; Ferritin; Funding; Goals; HIV; HIV Envelope Protein gp120; HIV-associated neurocognitive disorder; Hippocampus; Homeostasis; Human; Impaired cognition; In Vitro; Inflammation; Inhibitory Synapse; Iron; Iron Chelation; Iron-Binding Proteins; Learning; Life Style; Macaca; Maintenance; Measurement; Measures; Mediating; Mediator; Membrane Microdomains; Memory; Modeling; Molecular; Monitor; Morphine; Morphology; Neurons; Neurotoxins; Opioid; Pathway interactions; Patients; Performance; Prefrontal Cortex; Property; Protein Family; Proteins; Proteolysis; Rattus; Recording of previous events; Recovery; Regulation; Research; Rodent; Rodent Model; Role; SIV; Signal Transduction; Simplexvirus; Stromal Cell-Derived Factor 1; Structure; Substance abuse problem; Synapses; Testing; Therapeutic; Tissues; Up-Regulation; Vertebral column; Viral; Viral Proteins; abeta oligomer; amyloid precursor protein processing; amyloidogenesis; anti aging; beta secretase; brain tissue; chemokine; cognitive performance; cognitive task; comorbidity; density; excitotoxicity; in vivo; inhibitor; iron metabolism; memory process; neuronal transport; neuropathology; neurotoxic; neurotransmission; novel; opioid abuse; opioid use; preservation; prevent; protein degradation; protein expression; secretase; synergism; tool

Project Summary/Abstract HIV-associated neurocognitive disorders (HAND) persist in virally suppressed patients. HAND is a heterogeneous disease that is characterized by chronic low-level inflammation, excitotoxicity, presence of neurotoxic HIV proteins, altered APP processing, and other factors that aggravate neuronal structure and function. Opioid use is common among HIV+ patients and thought to contribute to HAND, although this remains controversial. Studies from the previous funding period suggest that morphine can augment HAND by altering APP processing through a novel, iron-dependent pathway. Toxic APP cleavage products are known to reduce dendritic spines in several brain areas, which are critical mediators of learning and memory. Surprisingly, the effects of APP cleavage products on dendritic spines of the prefrontal cortex (PFC), which is an area of critical importance to HAND, have not been studied in depth. This project will elucidate the role of altered APP processing in morphine and HIV-induced neuronal deficits in the PCF. Studies will unravel the interaction between HIV and Aβ proteins and determine whether morphine can contribute to alteration of APP processing and spines in HAND. Research in aim 1 will concentrate on the effect of Aβ oligomers on dendritic spine structure and function in PFC neurons, in the presence and absence of HIV neurotoxins or morphine. These in vitro and in vivo studies will define meaningful changes in dendritic spine density/morphology/turnover in PFC neurons, and provide a full assessment of exogenously added Aβ actions in this critical brain area (the role of endogenous Aβ will be further tested in aim 3). The main goal of aim 2 is to establish the extent to which µ-opioids can affect amyloidogenesis through modulation of neuronal iron. These mechanistic studies are based on our recent discoveries suggesting a role for iron in morphine-mediated dendritic spine reduction in cortical neurons. They are also supported by the finding that endosome deacidification leads to increase of cytosolic Fe2+ and Aβ. Importantly, cytosolic Fe2+ regulates APP expression whilst endolysosomal pH modulates protein degradation. In aim 3, we will employ newly generated molecular tools able to shift APP processing to the α-cleavage pathway or prevent APP cleavage by β-secretases. After functional testing in primary cultures, the most promising constructs will be expressed in PFC neurons of HAND animal models to determine how effectively they reduce Aβ levels in the presence of HIV proteins/morphine and if Aβ reduction contributes to recovery of PFC cognitive tasks. This proposal will shed light on iron-dependent mechanisms of accelerated cognitive decline in HIV+/opiate abusing subjects, which is becoming increasingly relevant as ART- treated patients live longer.

项目摘要/摘要 病毒抑制的患者持续存在HIV相关的神经认知障碍（手）。手是 异质疾病的特征是慢性低级炎症，兴奋性毒性，存在 神经毒性的HIV蛋白，改变的应用程序处理以及其他加剧神经元结构和的因素 功能。阿片类药物使用在艾滋病毒+患者中很常见，并被认为有助于手 仍然有争议。上一个资金期的研究表明吗啡可以通过 通过一种新颖的铁依赖性途径改变应用程序处理。已知有毒应用裂解产品 减少几个大脑区域的树突状刺，这是学习和记忆的关键介体。 令人惊讶的是，应用裂解产品对前额叶皮层（PFC）的树突状刺的影响， 尚未深入研究至关重要的领域。该项目将阐明 吗啡和HIV诱导的神经元中的APP处理改变了PCF中的定义。研究将揭示 HIV和Aβ蛋白之间的相互作用，并确定吗啡是否可以有助于APP的改变 手头的处理和刺。 AIM 1的研究将集中于Aβ低聚物对树突状的影响 在存在和不存在HIV神经毒素或吗啡的情况下，PFC神经元中的脊柱结构和功能。 这些体外和体内研究将定义树突状脊柱密度/形态/周转的有意义的变化 在PFC神经元中，并对在此关键大脑区域中的外源添加的Aβ作用进行了全面评估（ 内源性Aβ的作用将在AIM 3中进一步测试。目标2的主要目标是确定 哪种阿片类药物可以通过调节神经元铁来影响淀粉样蛋白发生。这些机械研究 基于我们最近的发现表明铁在吗啡介导的树突状脊柱还原中的作用 在皮质神经元中。他们也得到了以下发现的支持，即内体脱钩会导致增加 胞质Fe2+和Aβ。重要的是，胞质Fe2+调节APP表达，而内侧溶血pH 调节蛋白质降解。在AIM 3中，我们将采用新生成的分子工具来转移应用 加工到α-切解途径或防止β分泌酶的应用裂解。在功能测试之后 主要培养物，最有希望的结构将在手动模型的PFC神经元中表达 确定在HIV蛋白/吗啡存在下它们如何有效降低Aβ水平以及Aβ的降低。 有助于恢复PFC认知任务。该建议将阐明依赖铁的机制 艾滋病毒+/阿片类药物的认知能力下降加速，这变得越来越重要 治疗的患者寿命更长。