COMPLEMENT C1q MEDIATES THE MICROGLIAL ELIMINATION OF SYNAPSES INDUCED BY AMYLOID

项目摘要 尽管淀粉样蛋白诱导的神经炎症显著损害了海马区突触的可塑性 和认知功能，其潜在的机制只被部分了解。长期目标是 确定淀粉样蛋白诱导的炎症导致突触的分子和细胞机制 功能障碍和丢失为开发新的、临床有效的治疗方法提供了新的机会 痴呆的治疗或预防痴呆症的本申请的目的是确定调节和功能 补体C1q在小胶质细胞介导的海马谷氨酸能突触修剪中的作用。初级阶段 假设淀粉样蛋白纤维激活的小胶质细胞优先清除海马区的谷氨酸能 突触--啮齿类动物谷氨酸能突触中C1q表达增加所介导的过程 阿尔茨海默病(AD)模型。进一步推测mGluR-蛋白磷酸酶2A的激活 (PP2A)信号将触发脆性X智力低下蛋白(FMRP)的去磷酸化，从而 促进C1q突触表达和小胶质细胞清除海马谷氨酸能 AD啮齿动物模型中的突触。提出这项研究的理由是，机械论 了解小胶质细胞介导的海马谷氨酸能突触的消除可能有助于 对确定随后开发新的预防性或非传染性疾病的目标有意义 痴呆症的治疗干预。核心假设将通过追求三个具体目标来检验：1) 小胶质细胞修剪在淀粉样蛋白诱导的谷氨酸能突触功能障碍中的作用 2)确定补体C1q如何介导谷氨酸能突触的小胶质细胞修剪；以及3) 确定谷氨酸突触中C1q上调的机制。多形态的， 分子、电生理和行为方法将被用来评估小胶质细胞的偏好 淀粉样蛋白纤维诱导的谷氨酸能突触的消除及分子检测 这一病理过程在AD啮齿动物模型中的作用机制及功能意义。建议数 在PI看来，这项研究是创新的，因为它第一次聚焦于小胶质细胞的作用 AD模型中海马谷氨酸能突触的优先修剪。建议数 研究具有重要意义，因为预计它将构成一系列研究的第一步， 最终导致开发治疗或预防淀粉样蛋白相关的新的有效方法 痴呆症患者的记忆缺陷。

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.