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）：衰老的炎症是一个系统性事件，会影响大脑衰老的生理相关性。炎症途径与阿尔茨海默氏病（AD）密切相关，并且强烈建议使用病理疾病过程，即使使用抗炎药的临床试验并不有前途。尽管可能无法防止AD中的炎症过程，但可能可以刺激炎症级联反应的分辨率。在炎症的最后阶段，专门的促分解介体（SPM）积极参与炎症反应的下调。尽管在周围免疫系统中进行了很好的研究，但SPM直到最近才在脑组织中检测到。我们的发现表明，在AD患者的脑脊液（CSF）以及海马后术后组织中，SPMS及其合成酶和受体的显着改变。但是，尚未探索解决级联对AD神经病理学的特定影响，或者尚未探索其与认知下降的潜在相关性。 CSF数据清楚地表明，AD的SPM显着降低，从未受损的MCI和AD患者中，SPM的SPM受体在AD患者的海马形成中具有强烈的染色模式。我们是第一个报告AD和年龄匹配的对照人样品中SPM途径成分的分布和水平的人。在这项修订的提案中，我们希望研究分辨率级联，CSF和来自具有不同认知障碍水平的人（目标1）和验尸组织（AIM 2）的人类的作用（AIM 2），以确定可以作为AD的早期生物标志物以及可以增强AD的早期生物标志物，是否可以增强AD的AD和AD CONCIE cONCIENCON的结果。该提议的总体假设是：SPMS及其受体在AD患者的大脑中受到调节，并与痴呆程度相关。 CSF或血浆中SPM的测量可用作大脑中AD变性和痴呆症的生物标志物。我们提出了两个具体目的：在AIM 1中，CSF和血浆炎症解决因子的水平将与SCI，MCI和AD患者的特定认知和神经病理学措施相关，并且在AIM 2中，我们建议SPMS和相关分子与淀粉样蛋白斑块的负载和/或无关的群体相关。 CSF和血浆样本将与来自Karolinska记忆诊所（Schultzberg实验室）的一组患者的认知表现以及双重标记以及验化后组织（Granholm实验室）中的立体细胞计数的双重标记将产生足够的鼠标，以确定鼠标的实验，以促进群体的依赖，以促进型号，以促进型号，以促进型号，以促进型号，以促进型号，以促进型号，以促进构造的依从AD模型。