Mechanisms of Interferon-alpha Neurotoxicity

干扰素-α神经毒性的机制

• 批准号: 10158400
• 负责人: WILLIAM R TYOR
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10158400
• 关键词: AIDS dementia; AMPA Receptors; Address; Affect; Aftercare; Alzheimer' s Disease; Architecture; Basic Science; Behavior; Behavioral; Belief; Brain; Cerebrospinal Fluid; Clinical; Clinical Sciences; Clinical Trials; Cognition; Cognition Disorders; Country; Data; Dendrites; Dendritic Spines; Development; Disease; Disease model; Event; Exhibits; Exposure to; Future; Glutamate Receptor; HIV; HIV Infections; HIV therapy; HIV-associated neurocognitive disorder; Human; IFNAR1 gene; Impaired cognition; In Vitro; Incidence; Individual; Interferon-alpha; Intracellular Signaling Proteins; Investigation; Lead; Length; Link; Long-Term Depression; Mediating; Modeling; Morbidity - disease rate; Mus; N-Methyl-D-Aspartate Receptors; Neurocognitive Deficit; Neurons; Pathogenesis; Patients; Preclinical Testing; Proteomics; Rattus; SCID Mice; Signal Transduction; Signaling Protein; Societies; Synapses; Testing; Toxic effect; Translational Research; Validation; Vertebral column; Western Blotting; Work; age related; antiretroviral therapy; beta catenin; cognitive function; cost; effective therapy; improved; in vivo; interferon alpha receptor; mild cognitive impairment; mortality; mouse model; neurocognitive disorder; neurotoxic; neurotoxicity; novel; novel strategies; novel therapeutics; object recognition; overexpression; pre-clinical; prevent; receptor; receptor expression; receptor internalization; restoration; scaffold; screening; side effect; tool; type I interferon receptor

Worldwide there are over 35 million individuals living with HIV. As many as 50% of these HIV-infected individuals will develop HIV associated neurocognitive disorders (HAND), despite combined antiretroviral therapy (cART). Yet, since the advent of cART the incidence of HIV associated dementia, the most severe form of HAND, has diminished and represents less than 5% of HAND in countries like the US where cART is available. Therefore, mild forms of HAND, such as Asymptomatic Neurocognitive Impairment and Mild Neurocognitive Disorder, now predominate. Eventually these mild forms of HAND lead to HIV associated dementia and its severe consequences. In addition, because HIV-infected individuals are living longer, they are susceptible to age related diseases like Alzheimer’s disease, which can exacerbate HAND. Consequently, adjunctive therapies [to cART] must be developed. Interferon-alpha (IFNα) is elevated in the cerebrospinal fluid of HAND patients and correlates with cognitive dysfunction. Studies, including both clinical and basic, have established that IFNα is neurotoxic causing cognitive dysfunction and neuronal dendritic abnormalities. Our investigations suggest that IFNα could be a target for adjunctive therapies for HAND. A model of HAND in SCID mice was developed and forms an important part of the translational component of this proposal. This model demonstrates behavioral similarities to HAND in humans. The model has been useful in studying pathogenesis and the development of novel treatments. Recent improvements using object recognition testing before and after treatment enable us to determine reversal of behavioral abnormalities by novel therapies. This aspect of the model is particularly important because it reflects mild cognitive impairment in humans with HAND, the most common forms, and thus models conditions occurring in human clinical trials. As a result, the HAND model represents a valuable tool for pre-clinical screening of novel adjunctive therapies. Also, IFNα is elevated in brains of HAND mice and blocking IFNα in HAND mice is an effective treatment that may prove effective in HAND patients. Nevertheless, neutralizing IFNα in humans may not be ultimately practical due to potential side effects. Therefore, rat neuronal cultures are used to study the mechanisms of IFNα neurotoxicity. By studying the mechanisms of IFNα neurotoxicity, novel approaches to treatment of HAND, and perhaps other cognitive disorders, may be developed. Studies have shown that IFNα neurotoxicity is mediated through both the IFNα receptor (IFNAR) and the NMDA receptor (NMDAR). Rat neurons exposed to IFNα exhibit decreases in dendritic length and branching. Recent work demonstrates decreased PSD-95 puncta along dendrites, suggesting more specific mechanisms of toxicity. Proteomics demonstrate decreases in Arf1, Cdc42, and β-catenin, which are critical intracellular signaling proteins that are intimately involved in dendritic spine scaffolding. Arf1 decreases shown by proteomics have been verified through Western blotting. PSD-95 stabilizes NMDAR and AMPA receptors and thus PSD-95 decreases after IFNα potentially link it to Arf1, Cdc42 and possibly β-catenin. After validation that Cdc42 and β-catenin are decreased, we will overexpress all of them [individually] in neuronal cultures exposed to IFNα to determine if overexpression corrects PSD-95 decreases. We also hypothesize that because IFNα decreases PSD-95 on the spine, this leads to internalization of AMPA receptors both in vitro and in vivo. This ultimately results in disruption of neuronal networks, decreased plasticity, and long-term depression leading to poor cognition. We plan to investigate the relative contribution of the IFNAR and NMDAR to these effects, with the ultimate belief that both receptors contribute and that any future adjunctive treatments for HAND will need to address both receptors.

在全球范围内，有超过3500万人感染了艾滋病毒。这些HIV感染的多达50％ 个体将发展与HIV相关的神经认知障碍（手），合并的抗逆转录病毒 治疗（购物车）。然而，自货车冒险以来，艾滋病毒相关痴呆症的事件是最严重的 手的形式减少了，在美国等美国等国家 /地区的手不到5％ 可用的。因此，轻度的手，例如不对称的神经认知障碍和轻度 神经认知障碍，现在占主导地位。最终，这些温和的手形式导致艾滋病毒相关 痴呆症及其严重的后果。此外，由于感染了艾滋病毒的人的寿命更长，所以他们是 容易受到与年龄相关的疾病的影响，例如阿尔茨海默氏病，可能会加剧手动。最后， 必须开发辅助疗法。干扰素-alpha（IFNα）在脑脊液中升高 手动患者，与认知功能障碍相关。包括临床和基础在内的研究具有 确定IFNα是神经毒性，导致认知功能障碍和神经元树突异常。我们的 研究表明，IFNα可能是手工辅助疗法的靶标。 开发了SCID小鼠的手模型，并构成了翻译的重要组成部分 该提案的组成部分。该模型证明了与人类交手的行为相似性。模型 一直在研究发病机理和新治疗的发展。最近的改进 使用治疗前后的对象识别测试使我们能够确定行为的逆转 新型疗法异常。模型的这一方面尤其重要，因为它反映了中间 人类的认知障碍是手，最常见的形式，因此模型发生在 人类临床试验。结果，手模型代表了新型临床前筛查的有价值的工具 辅助疗法。同样，在手小鼠的大脑中，IFNα升高并阻塞手小鼠的IFNα是一种 有效的治疗方法可能对手动患者有效。然而，在人类中中和IFNα可能 由于潜在的副作用，最终不实用。因此，大鼠神经元培养物用于研究 IFNα神经毒性的机制。通过研究IFNα神经毒性的机制，新的方法 可以发展手的治疗，也许还有其他认知障碍。 研究表明，IFNα神经毒性是通过IFNα受体（IFNAR）和 NMDA受体（NMDAR）。暴露于IFNα暴露的大鼠神经元的树突状长度下降和 分枝。最近的工作表明，沿树突的PSD-95次点减少，表明更具体 毒性机制。蛋白质组学在ARF1，Cdc42和β-catenin中表现出下降，这是关键的 细胞内信号传导蛋白与树突状脊柱脚手架密切相关。 ARF1下降显示 通过蛋白质组学已通过蛋白质印迹验证。 PSD-95稳定NMDAR和AMPA接收器 因此，IFNα可能将其与ARF1，CDC42和可能的β-catenin联系起来后，PSD-95降低。验证后 Cdc42和β-catenin正在下降，我们将在神经元培养物中（单独）过表达它们 暴露于IFNα以确定过表达是否纠正PSD-95的下降。 我们还假设，由于IFNα在脊柱上降低了PSD-95，这导致了内在化 体外和体内的AMPA受体。这最终导致神经元网络中断，改善了 可塑性和长期抑郁导致认知不良。我们计划调查 IFNAR和NMDAR都对这些影响，最终认为两个受体都有贡献，任何受体都 未来的手工辅助治疗将需要解决这两个接收器。