Postnatal toxicant exposure in 3xTgAD mice promotes gene x environment-related early alterations to neuroimmune epigenetic profiles  

作　　者：Annalise N.vonderEmbse Qing Hu Jamie C.De Witt 

机构地区：[1]Department of Pharmacology and Toxicology,Brody School of Medicine at East Carolina University,Greenville,NC 27834,USA

出　　处：《Neuroimmunology and Neuroinflammation》2020年第4期345-359,共15页神经免疫与神经炎症（英文版）

基　　金：This work was supported by the Harriet and John Wooten Laboratory for Alzheimer’s and Neurodegenerative Diseases Research(https://www.ecu.edu/cs-dhs/wootenlab/).The funding body provided access to the 3xTgAD transgenic and wildtype mice used in the study.

摘　　要：Aim:The purpose of this study was to evaluate sex-biased,maladaptive changes to epigenetic regulation critical for development of neuroimmune crosstalk resulting from an early-life toxicant exposure previously associated with increased susceptibility to later-life neurodegeneration.Methods:An evaluation of early-life gene x environment(GxE)interactions was performed in a mouse model of Alzheimer's disease(Tg)orally exposed to lead acetate(Pb)from postnatal day(PND)5-9.Following exposure,immunohistochemical analysis was used to evaluate hippocampal expression of DAP12,a marker for perinatal microglia related to microglial-mediated postnatal synaptic pruning of neurons.Altered profiles of three microRNAs critical to homeostatic microglia:neuron signaling(miR-34a,miR-124,miR-132)were measured by qRT-PCR.Results:Atypical and deleterious expression patterns in Pb-exposed Tg mice were detected with significant female bias by PND 10.Early exposure to Pb resulted in the upregulation of miR-124,a microRNA involved in microglial quiescence,as well as miR-34a,involved in p53-dependent apoptosis and decreased phagocytosis,by PND 21 and during a period of microglial-mediated synaptic pruning specific to females.In addition,we observed a sustained,imbalanced upregulation of miR-132 in Pb-exposed Tg females as well as decreased expression of DAP12.Conclusion:This study demonstrates the exacerbating effects and early manifestation of GxE interactions in this model.Furthermore,these findings underscore a period of female-specific vulnerability to epigenetic maladaptation during postnatal development,with implications on the faulty later-life adaptability of neuroimmune signaling.Further investigation is warranted to evaluate the persistence and relative contribution of these early influences on the etiopathology of Alzheimer's disease.

关 键 词：MicroRNA MICROGLIA Alzheimer’s disease developmental origins of adult disease 

分 类 号：R73[医药卫生—肿瘤]