title: The blockage of the Nogo/NgR signal pathway in microglia alleviates the formation of Aβ plaques and tau phosphorylation in APP/PS1 transgenic mice.
abstract: BACKGROUND
  Alzheimer's disease (AD) is characterized by extracellular β-amyloid (Aβ) plaques, neurofibrillary tangles (NFTs), and microglia-dominated neuroinflammation. The Nogo/NgR signal pathway is involved in AD pathological features, but the detailed mechanism needs further investigation. Our previous studies have confirmed that the activation of NgR on microglia by Nogo promotes the expression of proinflammatory cytokines and inhibits cell adhesion and migration behaviors. In the present study, we investigated the effects of Nogo/NgR signaling pathway on the pathological features of AD and possible mechanisms.
  
  
  METHODS
  After NEP1-40 (a competitive antagonist of Nogo/NgR pathway) was intracerebroventricularly administered via mini-osmotic pumps for 2 months in amyloid precursor protein (APP)/PS1 transgenic mice, plaque load, tau phosphorylation, and inflammatory responses were determined. After primary mouse neurons were exposed to the conditioned medium from BV-2 microglia stimulated by Nogo, the production of Aβ and phosphorylation of tau was quantified by ELISA and western blot.
  
  
  RESULTS
  Inhibition of the Nogo/NgR signaling pathway ameliorated pathological features including amyloid plaques and phosphorylated levels of tau in APP/PS1 mice. In addition, after treatment with the conditioned medium from BV-2 microglia stimulated by Nogo, Aβ production and tau phosphorylation in cultured neurons were increased. The conditioned medium also increased the expression of APP, its amyloidogenic processing, and the activity of GSK3β in neurons. The conditioned medium was also proinflammatory medium, and the blockage of the Nogo/NgR pathway improved the neuroinflammatory environment in APP/PS1 mice.
  
  
  CONCLUSIONS
  Taken together, the neuroinflammation mediated by Nogo/NgR pathway in microglia could directly take part in the pathological process of AD by influencing the amyloidogenesis and tau phosphorylation. These results contribute to a better understanding of AD pathogenesis and could offer a new therapeutic option for delaying the progression of AD.
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. 166387335@qq.com.
authors.forename: Yinquan
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. 424686924@qq.com.
authors.forename: Lemeng
authors.initials: L
authors.lastname: Yao
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. lichenhui190@163.com.
authors.forename: Chenhui
authors.initials: C
authors.lastname: Li
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. chayu.wj@163.com.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. 175206551@qq.com.
authors.forename: Jianing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. 1065239298@qq.com.
authors.forename: Shujian
authors.initials: S
authors.lastname: Chen
authors.affiliation: School of Pharmacology and Medical Sciences, University of South Australia, Adelaide, SA, 5000, Australia. zhou0010@gmail.com.
authors.forename: Xin-Fu
authors.initials: XF
authors.lastname: Zhou
authors.affiliation: Jiangsu Key laboratory of Drug Screening, China Pharmaceutical University, 24 Tongjiaxiang Street, Nanjing, 210009, China. hliao@cpu.edu.cn.
authors.forename: Hong
authors.initials: H
authors.lastname: Liao
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D017077:Culture Media, Conditioned; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects*; D009185:Myelin Proteins / Q000494:pharmacology*; D000070798:Nogo Proteins / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017077:Culture Media, Conditioned; D009185:Myelin Proteins; C509624:NEP1-40 protein, human; D000070798:Nogo Proteins; D010446:Peptide Fragments; D016875:tau Proteins