Explore the Comparative Biology on Effects of Skin Ulceration on AD-Pathological Neurodegeneration

探索皮肤溃疡对 AD 病理性神经变性影响的比较生物学

• 批准号: 10043564
• 负责人: Song Hong
• 金额: $ 40.43万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10043564
• 关键词: Affect; Age; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; American; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Astrocytes; Behavior; Biological; Blood Circulation; Brain; Brain Injuries; Chronic; Comparative Biology; Data; Dementia; Dependence; Development; Docosahexaenoic Acids; Elderly; Enzymes; Genes; Goals; Hippocampus (Brain); Human; Impaired cognition; Infiltration; Inflammation; Inflammatory; Intervention; Ischemia; Knowledge; Leukocytes; Measures; Mediator of activation protein; Microglia; Minor; Modeling; Molecular; Mus; Nerve Degeneration; Neurons; Omega-3 Fatty Acids; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phagocytosis; Phase; Phenotype; Physiological; Pilot Projects; Prevalence; Publishing; Rattus; Reperfusion Therapy; Resolution; Risk; Series; Skin; System; Testing; Varicose Ulcer; abeta deposition; aged; aqueous; chronic wound; comparative; cytokine; decubitus ulcer; diabetic ulcer; improved; innovation; insight; lipid mediator; macrophage; multidisciplinary; neuroinflammation; nutritional supplementation; peripheral blood; pressure; prevent; response; skin ulcer; tau Proteins

ABSTRACT This application is in response to “PAR-17-039 Comparative Biology of Neurodegeneration”. Many aged Americans who suffer from Alzheimer’s disease (AD) also suffer from chronic skin ulcers. However, the effects of chronic skin ulceration on AD pathogenesis are poorly understood, leaving a gap in our knowledge. Inflammation-resolving (pro-resolving) lipid mediators [resolvin D1 (RvD1) and resolvin D5 (RvD5)] are present in healthy human and mouse brains. RvD1 and RvD5 are endogenous and produced by endogenous enzymes from ω-3 DHA. RvD1 or RvD5 switches macrophages (Ms) of AD patients to an M2 anti-inflammatory reparative phenotype and reverses the Aβ-induced M expression of inflammatory cytokines. Our pilot data suggest that the chronic pressure ulceration (PU) induced reduction of RvDs (the inflammation-resolving capacity) increases brain neuroinflammation and explains the PU promotion of AD-pathological neurodegeneration in 5xFAD mice. We hypothesize that chronic PU increases AD-pathological neurodegeneration and that this increase occurs at least partly via induction of chronic inflammation and reduction of inflammation-resolving capacity, manifested as the reduced levels of pro-resolving lipid mediators, including RvD1 and RvD5, both systemically and in brains. We will test our hypothesis via comparative biological approaches using both mouse and rat models of AD. Aim 1. We will induce chronic pressure ulceration (PU) in the skin of 5xFAD mice and TgF344-AD rats by pressure (ischemia/reperfusion) and compare results from these mice and rats in the following studies: 1A) Determine chronic PU effects on brain A- and/or tau-pathology-associated neurodegeneration and behavior readout (cognitive dysfunction) as well as potential age-dependence for these effects. 1B) Determine the reduction of inflammation-resolving capability in brains and systemic circulation as chronic PU effects on AD-pathological neurodegeneration. We will measure the pro-resolving capacity represented by targeted pro-resolving lipidomes (resolvin D-series) and inflammation status represented by targeted pro-inflammatory lipidome and cytokines. 1C) Decipher the chronic PU-induced activation of microglia and astrocytes and infiltration of blood leukocytes in brains in AD neurodegeneration. 1D) Modulate the inflammation-resolving capacity and inflammation by intranasal treatment of 5xFAD mice and TgF344-AD rats with RvD1 or RvD5 and compare the outcome to the results of 1A to 1C. Overall impact: This study will provide initial phase mechanistic knowledge that chronic PU exacerbates AD-neurodegeneration by reducing inflammation-resolving capability in circulation system and brains. It will determine how the responses of different animal species to chronic PU in the inflammation resolution of brains and systematic circulation affect AD neurodegeneration and onset. This R21 has considerable risk but will identify an innovative concept, mechanism, and intervention target to prevent and mitigate the risk imposed by chronic skin ulceration on AD-pathological neurodegeneration in the elderly.

抽象的 此申请是为了响应“PAR-17-039 神经退行性变的比较生物学”。很多上了年纪的 患有阿尔茨海默病 (AD) 的美国人还患有慢性皮肤溃疡。然而，影响 人们对慢性皮肤溃疡对AD发病机制的影响知之甚少，留下了我们的知识空白。 存在炎症消退（促消退）脂质介质 [resolvin D1 (RvD1) 和 resolvin D5 (RvD5)] 在健康的人类和小鼠大脑中。 RvD1 和 RvD5 是内源性的，由内源酶产生 来自 ω-3 DHA。 RvD1 或 RvD5 将 AD 患者的巨噬细胞 (Ms) 转变为 M2 抗炎药物 修复表型并逆转 Aβ 诱导的炎症细胞因子 Mf 表达。我们的试点数据 表明慢性压疮（PU）导致 RvD（炎症消退 容量）增加大脑神经炎症并解释 PU 促进 AD 病理 5xFAD 小鼠的神经退行性变。我们假设慢性 PU 会增加 AD 病理性 神经变性，这种增加至少部分是通过诱导慢性炎症和 炎症消解能力降低，表现为促消解脂质介质水平降低， 包括全身和大脑中的 RvD1 和 RvD5。我们将通过比较来检验我们的假设 使用 AD 小鼠和大鼠模型的生物学方法。目标1.我们将诱发慢性压力 压力（缺血/再灌注）和 5xFAD 小鼠和 TgF344-AD 大鼠皮肤溃疡（PU） 比较以下研究中这些小鼠和大鼠的结果： 1A) 确定 PU 对大脑的慢性影响 A-和/或 tau-病理学相关的神经变性和行为读数（认知功能障碍） 这些影响的潜在年龄依赖性。 1B) 确定炎症消退的减少 慢性 PU 对 AD 病理性神经变性的影响，影响大脑和全身循环的能力。我们 将测量以靶向促解析脂质组（resolvin D 系列）为代表的促解析能力，以及 由靶向促炎脂质组和细胞因子代表的炎症状态。 1C) 破译 AD 患者大脑中慢性 PU 诱导的小胶质细胞和星形胶质细胞激活以及白细胞浸润 神经变性。 1D) 通过鼻内调节炎症消解能力和炎症 用 RvD1 或 RvD5 治疗 5xFAD 小鼠和 TgF344-AD 大鼠，并将结果与 1A至1C。总体影响：本研究将提供慢性 PU 的初始阶段机制知识 通过降低循环系统的炎症解决能力而加剧 AD 神经变性， 大脑。它将确定不同动物物种对炎症中慢性PU的反应 大脑的分辨率和系统循环影响 AD 神经变性和发病。这个R21有 风险相当大，但会确定创新的理念、机制和干预目标来预防和 减轻慢性皮肤溃疡对老年人 AD 病理性神经变性造成的风险。