Resolving Factors in Alzheimers Disease

阿尔茨海默病的解决因素

• 批准号: 9134588
• 负责人: Ann-Charlotte Esther Granholm-Bentley
• 金额: $ 10.58万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9134588
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Anabolism; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Area; Autopsy; Binding; Biological Markers; Blood Circulation; Brain; Cell Count; Cells; Cerebrospinal Fluid; Clinic; Clinical; Clinical Trials; Cognitive; Complex; Coupled; Data; Dementia; Disease; Down-Regulation; Elderly; Enzymes; Epidemiologic Studies; Event; Exhibits; Funding; Goals; Health; Hippocampus (Brain); Homeostasis; Human; Immune; Immune system; Immunohistochemistry; Impaired cognition; In Vitro; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-12; Interleukin-6; Label; Laboratories; Lead; Link; Lipoxins; Measurement; Measures; Mediator of activation protein; Memory; Memory Loss; Neurodegenerative Disorders; Neurons; Outcome; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Phagocytosis; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Plasma; Play; Prevention; Process; Regulation; Reporting; Resolution; Role; Sampling; Senile Plaques; Serum; Severity of illness; Staging; Staining method; Stains; TNF gene; Tissues; Western Blotting; amyloid peptide; basal forebrain; base; brain tissue; cognitive performance; cohort; cytokine; entorhinal cortex; glial activation; inflammatory marker; mild cognitive impairment; mouse model; neurofibrillary tangle formation; neuron apoptosis; neuropathology; novel marker; peptide P; prevent; prospective; receptor; research study; synthetic enzyme; tau Proteins; treatment strategy

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）：炎症伴衰老是一种全身性事件，影响大脑中衰老的生理相关性。炎症通路与阿尔茨海默病（AD）密切相关，并且强烈建议参与病理疾病过程，即使使用抗炎剂的临床试验没有希望。虽然可能无法预防AD中的炎症过程，但相反可能刺激炎症级联反应的消退。在炎症的最后阶段，专门的促消退介质（SPM）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SPM最近才在脑组织中被检测到。我们的研究结果表明，显着改变SPM及其合成酶和受体，无论是在脑脊液（CSF）的AD患者，并在死后组织海马。然而，具体的影响，解决级联AD神经病理学，或其潜在的相关性与认知能力下降尚未探讨。CSF数据清楚地表明AD患者SPM以逐步方式从非受损、MCI和AD患者显著减少，并且AD患者海马结构中SPM受体的染色模式较强。我们是第一个报告AD和年龄匹配的对照人群样本中SPM途径组分的分布和水平。在本修订提案中，我们希望检查分辨级联在来自具有不同水平的认知障碍（Aim 1）的人的CSF和血浆中以及在死后组织（Aim 2）中的作用，以确定分辨级联是否可以作为AD的早期生物标志物，以及分辨刺激剂是否可以增强AD的结果或减少MCI向AD的转化。该建议的总体假设是：SPM及其受体在AD患者的大脑中失调，并与痴呆程度相关。CSF或血浆中SPM的测量可用作脑中AD变性和痴呆的可行生物标志物。我们提出了两个具体目标：在目标1中，CSF和血浆中炎症消退因子的水平将与SCI、MCI和AD患者的特定认知和神经病理学指标相关，在目标2中，我们建议检查SPM和相关分子是否与患有或不患有AD的老年人大脑脆弱区域中的淀粉样斑块负荷和/或缠结形成相关。CSF和血浆样品将与来自Karolinska记忆诊所（Schultzberg实验室）的患者队列中的认知表现相关，并且来自所涉及的两个脑库的死后组织（Granholm实验室）中的双标记结合体视学细胞计数将产生足够的数据以确定评价分辨级联是否需要在人类或小鼠AD模型中进行进一步的深入实验。