title: Suppression of LPS-induced tau hyperphosphorylation by serum amyloid A.
abstract: BACKGROUND
  Accumulation of hyperphosphorylated tau is a major neuropathological feature of tauopathies including Alzheimer's disease (AD). Serum amyloid A (SAA), an acute-phase protein with cytokine-like property, has been implicated in amyloid deposition. It remains unclear whether SAA affects tau hyperphosphorylation.
  
  
  METHODS
  Potential involvement of SAA in tau hyperphosphorylation was examined using intracerebral injection of SAA, and in Saa3 (-/-) mice receiving systemic administration of lipopolysaccharide (LPS). Induced SAA expression and microglial activation were evaluated in these mice using real-time PCR and/or immunofluorescence staining. Cultured primary neuronal cells were treated with condition media (CM) from SAA-stimulated primary microglial cells. The alteration in tau hyperphosphorylation was determined using Western blotting.
  
  
  RESULTS
  Saa3 is the predominant form of SAA proteins induced by LPS in the mouse brain that co-localizes with neurons. Overexpression of SAA by intracerebral injection attenuated tau hyperphosphorylation in the brain. Conversely, Saa3 deficiency enhanced tau phosphorylation induced by systemic LPS administration. Intracerebral injection of SAA also induced the activation of microglia in the brains. IL-10 released to CM from SAA-stimulated microglia attenuated tau hyperphosphorylation in cultured primary neurons. IL-10 neutralizing antibody reversed the effect of SAA in the attenuation of tau phosphorylation.
  
  
  CONCLUSIONS
  LPS-induced expression of SAA proteins in the brain leads to the activation of microglia and release of IL-10, which in turn suppresses tau hyperphosphorylation in a mouse model of systemic inflammation.
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. 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. 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. 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: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D016753:Interleukin-10 / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D000685:Serum Amyloid A Protein / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D017077:Culture Media, Conditioned; D016207:Cytokines; D008070:Lipopolysaccharides; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; C076498:Saa3 protein, mouse; D000685:Serum Amyloid A Protein; D016875:tau Proteins; D016753:Interleukin-10
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