Resolving Factors in Alzheimers Disease

描述（由申请人提供）：炎症伴衰老是一种影响大脑衰老生理相关因素的系统性事件。炎症途径与阿尔茨海默病（AD）密切相关，并且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。虽然可能不可能阻止AD的炎症过程，但可能有可能刺激炎症级联反应的解决。在炎症的最后阶段，专门的促化解介质（SPMs）积极参与炎症反应的下调。尽管在外周免疫系统中已经有了相当好的研究，但直到最近才在脑组织中发现SPMs。我们的研究结果表明，在阿尔茨海默病患者的脑脊液（CSF）和死后海马组织中，SPMs及其合成酶和受体都发生了显著的变化。然而，解决级联对阿尔茨海默病神经病理学的具体影响，或其与认知能力下降的潜在相关性尚未得到探讨。脑脊液数据清楚地表明，与未受损、MCI和AD患者相比，AD患者的SPM呈阶梯状显著减少，AD患者海马形成中的SPM受体呈强烈染色模式。我们首次报道了AD和年龄匹配的对照人类样本中SPM通路成分的分布和水平。在这个修订后的提案中，我们希望研究分解级联在不同程度认知障碍患者的脑脊液和血浆（Aim 1）以及死后组织（Aim 2）中的作用，以确定分解级联是否可以作为AD的早期生物标志物，以及分解刺激剂是否可以增强AD的预后或减少MCI向AD的转化。本提案的总体假设是：SPMs及其受体在AD患者的大脑中失调，并与痴呆程度相关。脑脊液或血浆中SPMs的测量可作为AD变性和脑痴呆的可行生物标志物。我们提出了两个具体目标：在Aim 1中，脑脊液和血浆消炎因子水平将与SCI、MCI和AD患者的特定认知和神经病理学指标相关；在Aim 2中，我们建议研究SPMs和相关分子是否与老年AD患者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（Schultzberg实验室）的一组患者的脑脊液和血浆样本将与认知表现相关，来自两个脑库的双重标记加上死后组织的立体细胞计数（Granholm实验室）将产生足够的数据，以确定评估解决级联是否值得在人类或AD小鼠模型中进一步深入实验。

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.