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

摘要 本申请是对“PAR-17-039神经变性的比较生物学”的回应。许多老年 患有阿尔茨海默病（AD）的美国人也患有慢性皮肤溃疡。但效果 慢性皮肤溃疡对AD发病机制的影响尚不清楚，在我们的认识中留下了空白。 存在炎症消退（促消退）脂质介质[消退素D1（RvD 1）和消退素D5（RvD 5）] 在健康的人类和老鼠的大脑中。RvD 1和RvD 5是内源性的，由内源性酶产生 ω-3 DHA RvD 1或RvD 5将AD患者的巨噬细胞（M2）转换为M2抗炎药 修复表型和逆转Aβ诱导的炎症细胞因子的M β表达。我们的试点数据 提示慢性压力性溃疡（PU）诱导RvD减少（炎症消退）， 能力）增加脑神经炎症，并解释了AD病理性PU促进 在5xFAD小鼠中的神经变性。我们假设慢性PU增加AD病理性 神经变性，并且这种增加至少部分地通过诱导慢性炎症而发生， 炎症消退能力降低，表现为促消退脂质介质水平降低， 包括RvD 1和RvD 5，在全身和大脑中。我们将通过比较来验证我们的假设。 使用AD的小鼠和大鼠模型的生物学方法。目标1。我们将诱导慢性压力 通过压力（缺血/再灌注）在5xFAD小鼠和TgF 344-AD大鼠的皮肤中形成溃疡（PU）， 在以下研究中比较来自这些小鼠和大鼠的结果：1A）确定慢性PU对脑的影响 以及与神经退行性变和/或tau病理学相关的神经退行性变和行为读出（认知功能障碍） 作为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病理性神经退行性变的影响。我们 将测量靶向促消退脂质体（消退素D系列）代表的促消退能力， 由靶向促炎脂质体和细胞因子代表的炎症状态。1C）解密 慢性PU诱导AD患者脑内小胶质细胞和星形胶质细胞活化及血白细胞浸润 神经变性1D）通过鼻内给药调节炎症消退能力和炎症 用RvD 1或RvD 5处理5xFAD小鼠和TgF 344-AD大鼠，并将结果与 1A到1C。总体影响：本研究将提供慢性PU 通过降低循环系统中的炎症消退能力而加剧AD-神经变性， 大脑它将确定不同动物种属对慢性PU的反应在炎症中的作用 脑和体循环的消退影响AD神经变性和发病。这款R21 相当大的风险，但将确定一个创新的概念，机制和干预目标，以防止和 减轻慢性皮肤溃疡对老年人AD病理性神经变性的风险。

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.