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)影响着每8个美国人中的1个，是美国第六大主要死亡原因。 近25万患有AD的人是退伍军人，最近的研究表明，退伍军人 患阿尔茨海默病的风险增加60%。行为变化，如激动和攻击性，困惑， 而戏剧性的人格变化，称为神经精神症状(NPS)，在AD患者中非常普遍， 对照顾者来说是极具挑战性的，给照顾者带来了巨大的情感和经济负担 对于AD患者，目前NPS的药物治疗，如抗精神病药物，镇静/催眠药物， 抗焦虑药物和抗抑郁药物通常有明显的不良影响，超过了这些药物的好处 治疗。因此，开发更好的治疗AD患者NPS的方法是至关重要的。大体上 在精神病学文献中，有一种新的观点认为炎症可能是致病原因的关键因素 精神状况，包括情绪障碍、严重抑郁、创伤后应激障碍(PTSD)，以及 甚至是精神分裂症。炎症过程如何导致阿尔茨海默病的神经精神症状还没有 已经研究过了。AD患者的神经精神表现发生在进行性 神经退行性疾病--阿尔茨海默病的特征--本身会产生大量炎症，所以我们 我认为了解炎症在NPS中的作用是至关重要的，特别是在AD的背景下，这是终极的 此应用程序的目标。 这一应用是基于一个新兴的想法，即脑部炎症可能会导致精神疾病 病症包括抑郁症、创伤后应激障碍(PTSD)，甚至精神分裂症。我们建议 治疗阿尔茨海默病患者神经炎症将预防或减少神经精神障碍的假设 焦虑、攻击性和冷漠等症状，并有可能找到更好的替代方案 治疗患有这些难以治疗的AD行为症状的退伍军人。 这笔赠款的前提是基于文献、我们公布的数据和新的初步数据，这些数据表明 针对白介素6(IL-6)信号的抗炎治疗将是有效的 在减弱相关模型中的NPS方面。目标1将询问炎症的证据是否预示风险增加 在一种新的AD小鼠模型(Riken研究所最近开发的Happ敲门小鼠)-小鼠中NPS的表达 已知表现出进行性的脑部炎症-并将表征老年AD小鼠在行为方面的表现 与人类NPS相关的任务。与行为相关的炎症标志物将包括血清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, 将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)在5、12和18个月龄时对脑片进行共聚焦荧光成像。男性和 将对雌性进行研究。目的2将验证三种抗炎策略针对IL-6和 下游信号将减少这些小鼠的NPS行为。治疗将包括：西尔图昔单抗 (Sylvant)，临床批准的抗IL-6免疫疗法；apocynin，NADPH氧化酶抑制剂；以及 Dismutazyme，一种小分子催化超氧化物歧化酶模拟物，被证明对小鼠和非小鼠有效。 人类灵长类动物。其目标将是确定这些抗炎治疗是预防还是减少 AD中的NPS。最终，如果减少脑部炎症的治疗可以预防或减少AD患者的NPS 患者，这可以支持正在使用的常规药物的替代或辅助治疗的开发， 从而提高AD患者的生活质量，减轻NPS的负担。最后，结果 这项研究可能表明，炎症的生物标志物可以作为NPS风险的预测因子，因此 改进AD中NPS临床研究的风险分层。

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.