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COMPLEMENT C1q MEDIATES THE MICROGLIAL ELIMINATION OF SYNAPSES INDUCED BY AMYLOID

补体 C1q 介导淀粉样蛋白引起的突触的微胶质消除

基本信息

批准号：
9559742
负责人：
Mohamed Naguib
金额：
$ 40万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9559742
关键词：
Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid Fibrils Behavior Behavioral Brain region Cerebral cortex Characteristics Classical Complement Pathway Clinical Cognition Disorders Complement Complement 1q Complement 2 Complement Activation Data Dementia Development Elderly Electrophysiology (science)FMR1 Functional disorder Generations Genetic Translation Glutamates Goals Health Hippocampus (Brain)Impairment Inflammation Inflammation Mediators Knowledge Lead Life Ligands Literature Mediating Memory Memory Loss Metabotropic Glutamate Receptors Microglia Mission Molecular Morphology Nature Neurodevelopmental Disorder Neurons Organism Pathogenesis Pathologic Processes Patients Play Preventive Intervention Process Production Protein Dephosphorylation Protein phosphatase Public Health Receptor Signaling Regulation Research Rodent Model Role Signal Transduction Synapses Synaptic plasticity Testing Therapeutic Intervention Time United States National Institutes of Health Up-Regulation amyloid induced neuroinflammation base cognitive function complement 1q receptor disability expectation innovation nervous system disorder neuroinflammation novel novel strategies prevent receptor synaptic pruning targeted treatment

项目摘要

Project Summary Although amyloid-induced neuroinflammation significantly impairs hippocampal synaptic plasticity and cognitive function, the underlying mechanisms are only partially understood. The long-term goal is to determine the molecular and cellular mechanisms whereby amyloid-induced inflammation leads to synaptic dysfunction and loss to provide new opportunities for development of novel, clinically effective approaches to treating or preventing dementias. The objective in this application is to determine the regulation and function of complement C1q in microglia-mediated pruning of hippocampal glutamatergic synapses. The primary hypothesis is that microglia activated by amyloid fibrils preferentially eliminate hippocampal glutamatergic synapses, a process mediated by the increased expression of C1q in the glutamatergic synapse in the rodent model of Alzheimer's Disease (AD). It is further hypothesized that activation of mGluR-protein phosphatase 2A (PP2A) signaling will trigger the dephosphorylation of fragile X mental retardation protein (FMRP), thus facilitating the synaptic expression of C1q and the microglial elimination of hippocampal glutamatergic synapses in the rodent model of AD. The rationale for the proposed research is that a mechanistic understanding of microglia-mediated elimination of hippocampal glutamatergic synapses is likely to contribute meaningfully toward the identification of targets for the subsequent development of new preventive or therapeutic interventions for dementia. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the role of microglia pruning in the dysfunction of glutamatergic synapses induced by amyloid fibrils; 2) Determine how complement C1q mediates the microglial pruning of glutamatergic synapses; and 3) Determine the mechanism responsible for C1q upregulation in glutamate synapses. Multiple morphological, molecular, electrophysiological and behavioral approaches will be applied to assess the microglial preferential elimination of glutamatergic synapse induced by the amyloid fibrils and to determine the molecular mechanism and functional significance of this pathologic process in rodent models of AD. The proposed research is innovative, in the PI's opinion, because it, for the first time, focuses on a role for microglial preferential pruning of hippocampal glutamatergic synapses in the setting of AD models. The proposed research is significant because it is expected to constitute the first step in a continuum of research that will ultimately lead to the development of novel effective approaches to treat or prevent amyloid associated memory deficiency in patients with dementia.

项目摘要虽然淀粉样蛋白诱导的神经炎症显著损害海马突触可塑性和认知功能，其潜在机制仅被部分理解。长期目标是确定淀粉样蛋白诱导的炎症导致突触功能障碍和损失，为开发新的临床有效方法提供新的机会，治疗或预防痴呆症。本申请的目的是确定调节和功能补体C1 q在小胶质细胞介导的海马神经元突触修剪中的作用主一种假说是淀粉样纤维激活的小胶质细胞优先消除海马神经元突触，这是一个由啮齿类动物突触中C1 q表达增加介导的过程阿尔茨海默病（AD）的模型。进一步假设mGluR-蛋白磷酸酶2A的激活（PP 2A）信号传导将触发脆性X智力低下蛋白（FMRP）的去磷酸化，促进C1 q的突触表达和小胶质细胞消除海马神经元突触在AD的啮齿动物模型。这项研究的基本原理是，了解小胶质细胞介导的海马神经元突触的消除可能有助于有意义地确定目标，以便随后开发新的预防性或对痴呆症的治疗干预。中心假设将通过追求三个具体目标来检验：1）确定小胶质细胞修剪在淀粉样蛋白诱导的突触功能障碍中的作用纤维; 2）确定补体C1 q如何介导突触的小胶质细胞修剪;以及3）确定谷氨酸突触中C1 q上调的机制。多种形态，分子，电生理和行为学方法将被应用于评估小胶质细胞的优先性，消除由淀粉样纤维诱导的突触能突触，并确定其分子机制。在AD的啮齿类动物模型中，这种病理过程的机制和功能意义。拟议在PI看来，这项研究是创新的，因为它第一次关注小胶质细胞的作用，在AD模型的设置中优先修剪海马神经元能突触。拟议研究是重要的，因为它预计将构成连续研究的第一步，最终导致开发新的有效方法来治疗或预防淀粉样蛋白相关的老年痴呆症患者的记忆缺陷。