title: MFG-E8 Selectively Inhibited Aβ-Induced Microglial M1 Polarization via NF-κB and PI3K-Akt Pathways.
abstract: Activated microglia are classified into two specific states: classically activated (M1) and alternatively activated (M2) subtypes. It is believed that the polarization of M1/M2 phenotype plays an important role in Alzheimer's disease (AD). However, the mechanisms regulating this process remain unclear. Thus, we addressed this question focusing on milk fat globule epidermal growth factor 8 (MFG-E8). MFG-E8 is a unique protein which can bind to microglia and regulate its inflammatory responses. It is speculated that it might play a role in the balance of microglial polarization. In the current study, we used fibril Aβ42 in vitro to stimulate mouse primary microglial cultures and found subsequent M1 marker expression, along with retained M2 marker production. Then, we discovered that MFG-E8 pretreatment reversed the increased trend of M1 markers and the decreased expression of M2 markers, which were induced by Aβ42. Moreover, MFG-E8 effects could be effectively blocked by an MFG-E8 antibody. Further analysis on the signaling pathways showed that NF-κB upregulation and Akt downregulation in microglial cultures were observed after Aβ42 incubation. And the alteration of these pathways could also be reversed by MFG-E8. We then assessed the effects of NF-κB and PI3K-Akt on M1/M2 alteration using their specific inhibitors. Pyrrolidine dithiocarbamate, a NF-κB inhibitor, inhibited M1 marker expression; moreover, LY294002, an Akt inhibitor, enhanced M1 marker expression. Our study indicated the regulatory role of MFG-E8 on microglia M1/M2 alteration for the first time, providing a basis for understanding the potential role of microglia activation in AD.
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, No. 92 Zheshan West Road, Wuhu, Anhui Province, 241000, People's Republic of China.|Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People's Republic of China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Shi
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People's Republic of China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Cai
authors.affiliation: Department of Neurology, Shaanxi Provincial People's Hospital, The Third Affiliated Hospital of Xi'an Jiaotong University, Medical College of Xi'an, Xi'an, Shaanxi Province, 710086, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Di
authors.affiliation: Department of Neurology, Zengcheng People's Hospital, Zengcheng, Guangdong Province, 511300, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People's Republic of China.
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Xu
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People's Republic of China.
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Qi
authors.affiliation: Department of Neurology, The First Affiliated Hospital, Yijishan Hospital of Wannan Medical College, No. 92 Zheshan West Road, Wuhu, Anhui Province, 241000, People's Republic of China.
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Guangdong Key Laboratory for Diagnosis and Treatment of Major Neurological Diseases, Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, 510080, People's Republic of China. fyn2012@126.com.
authors.forename: Yannan
authors.initials: Y
authors.lastname: Fang
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn; D000954:Antigens, Surface / Q000008:administration & dosage*; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008807:Mice, Inbred BALB C; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D008894:Milk Proteins / Q000008:administration & dosage*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; D008894:Milk Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; C490919:Mfge8 protein, mouse; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Aβ42; M1; M2; MFG-E8; Microglia