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: 9665155
• 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/9665155
• 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; Risk stratification; 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; 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.

阿尔茨海默病 (AD) 影响着八分之一的美国人，是美国第六大死因。 近 25 万 AD 患者是退伍军人，最近的研究表明，退伍军人 患 AD 的风险增加 60%。行为改变，例如烦躁、攻击性、混乱、 AD 患者中普遍存在显着的性格变化，即神经精神症状 (NPS)， 对护理人员来说极具挑战性，给护理人员带来巨大的情感和经济负担 对于 AD 患者，目前尚无 NPS 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具有显着的副作用，其副作用超过了它们的益处 治疗。因此，开发更好的 AD 患者 NPS 治疗方法至关重要。一般来说 精神病学文献中，有一个新兴的观点认为炎症可能是导致精神分裂症病因的关键因素。 精神疾病，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 的神经精神症状尚不清楚 被研究过。 AD 患者的神经精神表现发生在进行性进展的背景下 神经退行性疾病——AD 的特征——它本身会产生大量炎症，所以我们 相信了解炎症在 NPS 中的作用至关重要，特别是在 AD 的背景下，这是最终的治疗方法 此应用程序的目标。 该应用程序基于以下新观点：脑部炎症可能导致精神疾病 包括抑郁症、创伤后应激障碍（PTSD），甚至精神分裂症。我们建议 治疗 AD 患者的神经炎症将预防或减少神经精神疾病的假设 焦虑、攻击性和冷漠等症状，有可能找到替代方案和更好的方法 为患有这些难以治疗且往往具有破坏性的 AD 行为症状的退伍军人提供治疗。 这项资助的前提是基于文献、我们发布的数据和新的初步数据，这些数据表明 针对白细胞介素 6 (IL-6) 信号传导的抗炎治疗将是有效的 减弱相关模型中的NPS。目标 1 将询问炎症证据是否预示着风险增加 NPS 在新的 AD 小鼠模型（理研研究所最近开发的 hAPP 敲入小鼠）中的作用 - 小鼠 已知表现出进行性脑部炎症 - 并将表征老年 AD 小鼠的行为表现 与人类 NPS 相关的任务。与行为相关的炎症标志物包括血清 C- 反应蛋白和 IL-6，它们与许多精神疾病状态密切相关。此外， 通过量化激活的星形胶质细胞 (GFAP) 和小胶质细胞的数量来评估神经炎症 (Iba1) 使用三个年龄（5、12 和 18 个月）脑切片的共焦荧光成像。男性和 女性将被研究。目标 2 将检验以下假设：针对 IL-6 和 IL-6 的三种抗炎策略 下游信号传导将减少这些小鼠的 NPS 行为。治疗方法包括： 西妥昔单抗 （Sylvant），一种临床批准的抗 IL-6 免疫疗法；罗布麻宁 (Apocynin)，一种 NADPH 氧化酶抑制剂；和 Dismutazyme 是一种小分子催化超氧化物歧化酶模拟物，已被证明对小鼠和非 人类灵长类动物。目标是确定这些抗炎治疗是否可以预防或减少 AD 中的 NPS。最终，如果减少大脑炎症的治疗能够预防或减少 AD 中的 NPS 患者，这可以支持开发传统药物的替代疗法或辅助疗法， 从而改善 AD 患者的生活质量并减轻 NPS 负担。最后，结果 这项研究可能表明炎症的生物标志物可以用作 NPS 风险的预测因子，因此 改善 AD 中 NPS 临床研究的风险分层。