Resolving Factors in Alzheimers Disease

阿尔茨海默病的解决因素

• 批准号: 9388390
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 5万
• 依托单位: UNIVERSITY OF DENVER (COLORADO SEMINARY)
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388390
• 关键词: Resolving; Factors; Alzheimers; Disease

DESCRIPTION (provided by applicant): Inflammation with aging is a systemic event which affects physiological correlates of aging in the brain. Inflammatory pathways are closely linked to Alzheimer's disease (AD), and are strongly suggested to partake in the pathological disease process, even though clinical trials using anti-inflammatory agents have not been promising. Although it may not be possible to prevent inflammatory processes in AD, it may instead be possible to stimulate the resolution of the inflammatory cascade. In the last stage of inflammation, specialized pro-resolving mediators (SPMs) are actively involved in down-regulation of the inflammatory response. Albeit fairly well studied in the peripheral immune system, the SPMs have only recently been detected in brain tissue. Our findings suggest significant alterations in SPMs and their synthetic enzymes and receptors, both in cerebrospinal fluid (CSF) of patients with AD, and in postmortem tissue from the hippocampus. However, the specific influence of the resolving cascade on AD neuropathology, or its potential correlation with cognitive decline have not been explored. The CSF data clearly indicate a significant reduction in SPMs with AD, in a step-wise manner from non-impaired, MCI and AD patients, and a strong staining pattern for SPM receptors in the hippocampus formation in patients with AD. We are the first to report both distribution and levels of the SPM pathway components in AD and age-matched control human samples. In this revised proposal, we wish to examine the role of the resolving cascade, in CSF and plasma from humans with different levels of cognitive impairment (Aim 1) and in postmortem tissue (Aim 2) to determine whether the resolving cascade can serve as an early biomarker for AD, and whether resolving stimulating agents can enhance the outcome of AD or reduce conversion of MCI to AD. The overall hypothesis of this proposal is: SPMs and their receptors are dys-regulated in the brain of AD patients and correlate with degree of dementia. Measurements of SPMs in CSF or in plasma can be used as a viable biomarker for AD degeneration and dementia in the brain. We have proposed two specific aims: In Aim 1, CSF and plasma levels of inflammation resolving factors will be correlated with specific cognitive and neuropathological measures in SCI, MCI, and AD patients, and in Aim 2, we propose to examine whether SPMs and associated molecules correlate with amyloid plaque load and/or tangle formation in vulnerable areas of the brain in elderly individuals with or without AD. CSF and plasma samples will be correlated with cognitive performance in a cohort of patients from the Karolinska memory clinic (Schultzberg laboratory) and double labeling coupled with stereological cell counts in postmortem tissue (Granholm Laboratory) from the two brain banks involved will generate sufficient data to determine whether evaluating the resolving cascade warrants further in depth experiments in humans or mouse models of AD.

描述(由申请人提供)：与衰老相关的炎症是一种系统性事件，它影响大脑中衰老的生理相关因素。炎症途径与阿尔茨海默病(AD)密切相关，强烈建议参与病理疾病过程，尽管使用抗炎药的临床试验并不乐观。虽然可能无法阻止AD的炎症过程，但有可能刺激炎症级联反应的消退。在炎症的最后阶段，特殊的促分解介质(SPM)积极参与炎症反应的下调。尽管在外周免疫系统中进行了相当好的研究，但直到最近才在脑组织中检测到SPM。我们的发现表明，无论是在AD患者的脑脊液中，还是在海马区的死后组织中，SPM及其合成酶和受体都发生了显著的变化。然而，分解级联对AD神经病理的具体影响，或其与认知功能下降的潜在相关性还没有被探索。脑脊液数据清楚地表明，AD患者的SPM明显减少，在非受损的MCI和AD患者中，SPM以一种循序渐进的方式减少，AD患者海马区SPM受体的染色模式很强。我们首次报道了在AD和年龄匹配的对照组人类样本中SPM途径成分的分布和水平。在这个修订的方案中，我们希望研究不同程度认知损害的人的脑脊液和血浆(目标1)和死后组织(目标2)中分解级联的作用，以确定分解级联是否可以作为AD的早期生物标记物，以及分解刺激剂是否可以增强AD的转归或减少MCI向AD的转化。这一设想的总体假设是：SPM及其受体在AD患者的大脑中处于异常调节状态，并与痴呆程度相关。脑脊液或血浆中SPM的测定可作为脑内AD变性和痴呆的一个可行的生物标志物。我们提出了两个特定的目标：在目标1中，脑脊液和血浆中炎症分解因子的水平将与脊髓损伤、MCI和AD患者的特定认知和神经病理指标相关，在目标2中，我们建议研究SPM及其相关分子是否与患有或不患有AD的老年人大脑易损区域的淀粉样斑块负荷和/或缠结形成相关。来自卡罗林斯卡记忆诊所(舒尔茨堡实验室)的一群患者的脑脊液和血浆样本将与认知表现相关，来自两个相关脑库的双重标记与死后组织(格兰霍姆实验室)的立体细胞计数将产生足够的数据，以确定评估分辨率级联是否有理由在人类或小鼠AD模型中进行进一步的深入实验。