Mechanisms of Interferon-alpha Neurotoxicity

干扰素-α神经毒性的机制

• 批准号: 9886071
• 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/9886071
• 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.

全球有超过 3500 万艾滋病毒感染者。其中多达 50% 的 HIV 感染者 尽管联合抗逆转录病毒治疗，个体仍会出现与艾滋病毒相关的神经认知障碍（HAND） 疗法（cART）。然而，自从 cART 出现以来，艾滋病毒相关痴呆症的发病率有所下降，这是最严重的 形式的 HAND 已减少，在美国等开展 cART 的国家，其比例不足 5% 可用的。因此，轻度形式的 HAND，例如无症状神经认知障碍和轻度 神经认知障碍，现在占主导地位。最终，这些温和形式的 HAND 会导致与 HIV 相关的感染 痴呆症及其严重后果。此外，由于艾滋病毒感染者的寿命更长，他们 容易患上与年龄相关的疾病，例如阿尔茨海默氏病，这会加剧手部疾病。最后， 必须开发[cART]的辅助疗法。脑脊液中干扰素-α (IFNα) 升高 HAND 患者的患病率并与认知功能障碍相关。研究，包括临床和基础研究， 确定 IFNα 具有神经毒性，导致认知功能障碍和神经元树突异常。我们的 研究表明 IFNα 可能成为 HAND 辅助治疗的靶点。 开发了 SCID 小鼠的 HAND 模型，该模型构成了转化研究的重要组成部分。 本提案的组成部分。该模型展示了与人类 HAND 的行为相似性。型号 在研究发病机制和开发新疗法方面发挥了重要作用。最近的改进 在治疗前后使用物体识别测试使我们能够确定行为的逆转 新疗法的异常。模型的这一方面特别重要，因为它反映了温和的 人类患有手部认知障碍（最常见的形式），因此可以模拟发生在 人体临床试验。因此，HAND 模型代表了新药临床前筛选的宝贵工具。 辅助疗法。此外，HAND 小鼠大脑中的 IFNα 升高，阻断 HAND 小鼠的 IFNα 是一种有效的方法。 可能对 HAND 患者有效的有效治疗。然而，中和人类的 IFNα 可能 由于潜在的副作用，最终无法实现。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，新方法 可能会开发出针对 HAND 以及其他认知障碍的治疗方法。 研究表明，干扰素α的神经毒性是通过干扰素α受体（IFNAR）和干扰素介导的。 NMDA 受体（NMDAR）。暴露于 IFNα 的大鼠神经元表现出树突长度的减少和 分枝。最近的工作表明，沿树突的 PSD-95 斑点减少，表明更具体 毒性机制。蛋白质组学证明 Arf1、Cdc42 和 β-catenin 的减少，这是至关重要的 与树突棘支架密切相关的细胞内信号蛋白。显示 Arf1 减少 蛋白质组学分析已通过蛋白质印迹法得到验证。 PSD-95 稳定 NMDAR 和 AMPA 受体 因此，在 IFNα 可能与 Arf1、Cdc42 和可能的 β-catenin 连接后，PSD-95 会降低。验证后 如果 Cdc42 和 β-catenin 减少，我们将在神经元培养物中[单独]过度表达它们 暴露于 IFNα 以确定过度表达是否可以纠正 PSD-95 降低。 我们还假设，由于 IFNα 会降低脊柱上的 PSD-95，这会导致 AMPA 受体在体外和体内。这最终导致神经元网络的破坏，减少 可塑性差，长期抑郁导致认知能力差。我们计划调查的相对贡献 IFNAR 和 NMDAR 对这些作用的影响，最终相信这两种受体都有贡献，并且任何 未来 HAND 的辅助治疗将需要针对这两种受体。