title: Deficiency of macrophage migration inhibitory factor attenuates tau hyperphosphorylation in mouse models of Alzheimer's disease.
abstract: BACKGROUND
  Pathological features of Alzheimer's disease (AD) include aggregation of amyloid beta (Aβ) and tau protein. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has been implicated in the toxicity of aggregated Aβ. It remains unclear whether MIF affects hyperphosphorylation and aggregation of tau.
  
  
  METHODS
  The effects of MIF deficiency in tau hyperphosphorylation were examined in Mif (-/-) mice receiving intracerebroventricular (ICV) injection of streptozotocin (STZ) and in APP/PS1 transgenic mice mated with Mif (-/-) mice. MIF expression and astrocyte activation were evaluated in ICV-STZ mice using immunofluorescence staining. Cultured primary astrocytes were treated with high glucose to mimic STZ function in vitro, and the condition medium (CM) was collected. The level of tau hyperphosphorylation in neurons treated with the astrocyte CM was determined using Western blotting.
  
  
  RESULTS
  MIF deficiency attenuated tau hyperphosphorylation in mice. ICV injection of STZ increased astrocyte activation and MIF expression in the hippocampus. MIF deficiency attenuated astrocyte activation in ICV-STZ mice. CM from high glucose-treated WT astrocytes increased tau hyperphosphorylation in cultured primary neurons, an effect absent from Mif (-/-) astrocytes and WT astrocytes treated with the MIF inhibitor ISO-1. ISO-1 had no direct effect on tau phosphorylation in cultured primary neurons.
  
  
  CONCLUSIONS
  These results suggest that MIF deficiency is associated with reduced astrocyte activation and tau hyperphosphorylation in the mouse AD models tested. Inhibition of MIF and MIF-induced astrocyte activation may be useful in AD prevention and therapy.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. shuqinliky@163.com.
authors.forename: Shu-Qin
authors.initials: SQ
authors.lastname: Li
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. yuyang2011@sjtu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. hanjinzhao@sjtu.edu.cn.
authors.forename: Jin-Zhao
authors.initials: JZ
authors.lastname: Han
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. lotinos@sjtu.edu.cn.
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. fanhuasijin@sjtu.edu.cn.
authors.forename: Jin
authors.initials: J
authors.lastname: Liu
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. fengqian@sjtu.edu.cn.
authors.forename: Feng
authors.initials: F
authors.lastname: Qian
authors.affiliation: GlaxoSmithKline Research and Development Center, Shanghai, 201203, China. guohuang.g.fan@gsk.com.
authors.forename: Guo-Huang
authors.initials: GH
authors.lastname: Fan
authors.affiliation: Department of Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. Richard.bucala@yale.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China. yedequan@sjtu.edu.cn.|Institute of Chinese Medical Sciences, University of Macau, Macau, SAR, China. yedequan@sjtu.edu.cn.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Ye
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D005260:Female; D005947:Glucose / Q000494:pharmacology; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D061251:Primary Cell Culture; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D008263:Macrophage Migration-Inhibitory Factors; D016875:tau Proteins; D005947:Glucose