Novel treatments for neuropsychiatric symptoms in Alzheimers Disease (AD): targeting inflammatory injury using three translational anti-inflammatory strategies in a new AD model.

阿尔茨海默病 (AD) 神经精神症状的新疗法：在新的 AD 模型中使用三种转化抗炎策略来靶向炎症损伤。

• 批准号: 10043824
• 负责人: Laura L Dugan
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043824
• 关键词: Adverse effects; Affect; Age; Age-Months; Aggressive behavior; Agitation; Alzheimer' s Disease; Alzheimer' s disease care; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; American; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antidepressive Agents; Antipsychotic Agents; Anxiety; Astrocytes; Attenuated; Behavior; Behavioral; Behavioral Symptoms; Biological Markers; Brain; Brain imaging; C-reactive protein; Caregivers; Caring; Cause of Death; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Confusion; Data; Dementia; Deposition; Development; Direct Costs; Emotional; Encephalitis; Etiology; Exhibits; Family; Female; Financial Hardship; Glial Fibrillary Acidic Protein; Goals; Grant; Human; Immunofluorescence Immunologic; Immunotherapy; Individual; Inflammation; Inflammatory; Injury; Institutes; Interleukin-6; Knock-in; Knock-in Mouse; Literature; Major Depressive Disorder; Measures; Mental Depression; Mental disorders; Microglia; Modeling; Mood Disorders; Mus; NADPH Oxidase; Neurodegenerative Disorders; Pathway interactions; Patient Care; Patients; Performance; Personality; Pharmaceutical Preparations; Pharmacological Treatment; Phenotype; Plasma; Post-Traumatic Stress Disorders; Process; Production; Progressive Disease; Publishing; Quality of life; Regression Analysis; Reporting; Risk; Role; Schizophrenia; Serum; Signal Transduction; Slice; Superoxide Dismutase; Superoxides; Symptoms; Testing; Therapeutic; United States; Veterans; Wild Type Mouse; acetovanillone; aged; associated symptom; base; behavior test; design; fluorescence imaging; hypnotic; improved; inflammatory marker; inhibitor/antagonist; juvenile animal; male; mimetics; mouse model; neuroinflammation; neuropsychiatric symptom; neuropsychiatry; neurotoxicity; nonhuman primate; novel; overexpression; prevent; psychiatric symptom; risk stratification; sedative; side effect; small molecule; treatment effect; treatment strategy

Alzheimer’s disease (AD) affects 1 in 8 Americans, and is the sixth leading cause of death in the United States. Nearly a quarter of a million of those living with AD are Veterans, and recent studies have shown that Veterans have a 60% increased risk of developing AD. Behavioral changes, such as agitation and aggression, confusion, and dramatic personality changes, termed neuropsychiatric symptoms (NPS) are highly prevalent in AD patients, and are extremely challenging for caregivers, placing significant emotional and financial burdens on those caring for patients with AD, yet current pharmacological treatments for NPS, such as antipsychotics, sedative/hypnotics, anxiolytics, and antidepressants, often have significant adverse effects that outweigh the benefits of these treatments. Thus, it is critical to develop better therapeutic approaches to NPS in AD patients. In the general psychiatric literature, there is an emerging idea that inflammation may be a critical contributor to the etiology of psychiatric conditions including mood disorder, major depression, post-traumatic stress disorder (PTSD), and even schizophrenia. How inflammatory processes contribute to neuropsychiatric symptoms in AD has not yet been studied. Neuropsychiatric manifestations in AD patients occur in the context of a progressive neurodegenerative disease – the characteristic of AD - which produces substantial inflammation, itself, so we believe it is critical to understand the role of inflammation in NPS specifically in the context of AD, the ultimate goal of this application. This application is based on the emerging idea that brain inflammation may contribute to psychiatric conditions including depression, post-traumatic stress disorder (PTSD), and even schizophrenia. We propose the hypothesis that treating neuroinflammation in AD patients will prevent or decrease neuropsychiatric symptoms such as agitation, aggression, and apathy, with the potential of finding alternative and better treatments for Veterans with these difficult-to-treat and often devastating behavioral symptoms of AD. The premise for this grant is based on the literature, our published data, and new preliminary data, which show that anti-inflammatory treatment treatments directed at interleukin-6 (IL-6) signaling, specifically, will be effective in attenuating NPS in relevant models. Aim 1 will ask whether evidence of inflammation predicts increased risk of NPS in a new mouse model of AD (the hAPP knockin mice recently developed at the Riken Institute) - mice known to exhibit progressive brain inflammation - and will characterize how aged AD mice perform on behavioral tasks relevant to human NPS. Markers of inflammation to be correlated with behavior will include serum C- reactive protein and IL-6, which have been strongly associated with many psychiatric disease states. In addition, neuroinflammation will be assessed by quantifying the number of activated astrocytes (GFAP) and microglia (Iba1) using confocal fluorescence imaging of brain slices at three ages: 5, 12, and 18 months. Males and females will be studied. Aim 2 will test the hypothesis that three anti-inflammatory strategies targeting IL-6 and downstream signaling will reduce NPS behaviors in these same mice. Treatments will include: siltuximab (Sylvant), a clinically approved anti-IL-6 immunotherapy; Apocynin, a NADPH oxidase inhibitor; and Dismutazyme, a small molecule catalytic superoxide dismutase mimetic, shown to be effective in mice and non- human primates. The goal will be to determine whether these anti-inflammatory treatments prevent or reduce NPS in AD. Ultimately, if treatments which reduce inflammation in the brain prevent or decrease NPS in AD patients, this could support development of alternative or adjunct treatments to conventional drugs being used, thus improving the quality of life and decreasing the burden of NPS in patients living with AD. Finally, results from this study may suggest that biomarkers of inflammation could be used as predictors of NPS risk, thus improving risk stratification for clinical studies on NPS in AD.

阿尔茨海默氏病（AD）影响了八分之一的美国人，是美国第六大死亡原因。 近四分之一的广告居民是退伍军人，最近的研究表明，退伍军人 发展广告的风险增加了60％。行为变化，例如躁动和侵略，混乱， 在AD患者中，称为神经精神症状（NP）的人格变化很普遍， 并且对护理人员面临极大的挑战，在那些关怀的人身上施加了巨大的情感和财务燃烧 对于AD患者，但目前针对NP的药物治疗，例如抗精神病药，镇静/催眠药， 抗焦虑药和抗抑郁药通常会产生重大的不良影响，超过这些益处 治疗。这是至关重要的，为AD患者开发更好的NPS治疗方法至关重要。一般 精神科文学，有一个新兴的想法，即炎症可能是导致病因的关键因素 精神病病，包括情绪障碍，重度抑郁症，创伤后应激障碍（PTSD）和 甚至精神分裂症。炎症过程如何导致AD的神经精神症状 被研究了。 AD患者的神经精神表现出现在进行性的背景下 神经退行性疾病 - AD的特征 - 会产生强大的炎症，因此我们 认为在AD的背景下，了解炎症在NP中的作用至关重要，这是至关重要的 此应用程序的目标。 该应用是基于新兴的想法，即大脑感染可能有助于精神科 包括抑郁症，创伤后应激障碍（PTSD）甚至精神分裂症的疾病。我们建议 AD患者治疗神经炎症的假设将预防或减少神经精神病学 躁动，侵略性和冷漠等症状，有可能找到替代方案和更好的症状 这些难以治疗和经常毁灭性行为症状的退伍军人的治疗方法。 该赠款的前提是基于文献，我们已发布的数据和新的初步数据，这些数据表明 特别是针对白介素6（IL-6）信号传导的抗炎处理治疗将是有效的 在相关模型中衰减NP。 AIM 1会询问炎症预测的证据是否增加了风险 NP在新的AD鼠标模型中的NP（Happ敲门小鼠最近在Riken Institute开发）-MICE 已知会暴露于进行性脑部感染 - 并将表征老化的AD小鼠在行为上的表现 与人类NP相关的任务。与行为相关的炎症标记将包括血清C- 反应性蛋白质和IL-6，与许多精神病状态密切相关。此外， 神经炎症将通过量化活化的星形胶质细胞（GFAP）和小胶质细胞的数量来评估 （IBA1）使用三个年龄的脑切片的共聚焦荧光成像：5、12和18个月。男性和 女性将研究。 AIM 2将检验以下假设，即针对IL-6和的三种抗炎策略 下游信号传导将减少这些相同小鼠的NPS行为。治疗将包括：硅 （Sylvant），临床认可的抗IL-6免疫疗法； Apocynin，一种NADPH氧化物抑制剂；和 张甲策酶是一种小分子催化超氧化物歧化酶模拟酶，证明对小鼠和非 - 人类的素数。目的是确定这些抗炎治疗是否预防或减少 AD中的NP。最终，如果减轻大脑炎症的治疗预防或减少AD的NP 患者，这可以支持开发用于使用的常规药物的替代或辅助治疗， 改善了AD患者的生活质量并减少NP的燃烧。最后，结果 从这项研究中可能表明，炎症的生物标志物可以用作NPS风险的预测指标，因此 改善AD中NP临床研究的风险分层。