COMPLEMENT C1q MEDIATES THE MICROGLIAL ELIMINATION OF SYNAPSES INDUCED BY AMYLOID

项目总结

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.