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.

阿尔茨海默病（AD）影响了八分之一的美国人，是美国第六大死亡原因。