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.

全世界有超过3500万人感染了艾滋病毒。其中多达50%的人感染了艾滋病毒