title: Hydrogen sulfide down-regulates BACE1 and PS1 via activating PI3K/Akt pathway in the brain of APP/PS1 transgenic mouse.
abstract: BACKGROUND
  Endogenous hydrogen sulfide (H2S) may have multiple physiological functions in brain. Our previous study showed that H2S improved spatial memory impairment and decreased the production of Aβ in APP/PS1 transgenic mice. However, many of the underlying mechanisms are not still being elucidated. The aim of the present study is to investigate the neuroprotective mechanisms of H2S involving in the activity of β-secretase (BACE1), γ-secretase (PS1) and α-secretase (ADAM17).
  
  
  METHODS
  Morris water maze was used to measure the behavior change. The levels of Aβ40 and Aβ42 were quantified using colorimetric ELISA kits and immunohistochemical analysis. The levels of BACE1, PS1, ADAM17, pAkt, pp38MAPK, pERK and pJNK were tested by Western blot analysis in normal mice, APP/PS1 transgenic mice and 50μmol/kg-NaHS-treated transgenic mice. On the basis of exogenous H2S treatment, LY294002 (inhibitors of PI3K/Akt) or PD98059 (inhibitors of MAPK/ERK) was injected into lateral cerebral ventricle.
  
  
  RESULTS
  The levels of BACE1, PS1 and pp38MAPK were increased and ADAM17 were decreased in the APP/PS1 transgenic mice. After intraperitoneal administration of an H2S donor (NaHS) into APP/PS1 mice, the levels of BACE1, PS1 and pp38MAPK were reduced and ADAM17 increased. The level of pp38 MAPKs, pAkt and pERK1/2 was increased in APP/PS1 transgenic mice compared with normal mice (p<0.05). There was no difference in the expression of pJNK between AD transgenic mice and normal mice (p>0.05). These results demonstrated that LY294002 inhibited the effect of H2S on decreasing the BACE1 and PS1, reducing the level of Aβ and improving memory impairment in APP/PS1 transgenic mice. PD98059 had no influence on the expression of BACE1 and PS1.
  
  
  CONCLUSIONS
  H2S inhibits the expression of BACE1 and PS1 by activating PI3K/Akt pathway in AD.
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Chongqing 400016, China.
authors.forename: Xuan-Li
authors.initials: XL
authors.lastname: He
authors.affiliation: Department of Neurology, The University-Town Hospital of Chongqing Medical University, Chongqing 401331, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Yan
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Chongqing 400016, China.
authors.forename: Xiao-Shan
authors.initials: XS
authors.lastname: Chen
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Chongqing 400016, China.
authors.forename: Yun-Wen
authors.initials: YW
authors.lastname: Qi
authors.affiliation: Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, No. 1 Youyi Road, Chongqing 400016, China. Electronic address: yyanpro@163.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Neurology, Renmin Hospital, Hubei University of Medicine, Shiyan Renmin Hospital, No. 39 Chaoyang Middle Road, Shiyan, Hubei Province 442000, China. Electronic address: czy000806@163.com.
authors.forename: Zhiyou
authors.initials: Z
authors.lastname: Cai
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000072198:ADAM17 Protein; D006862:Hydrogen Sulfide
keywords: Alzheimer's; Hydrogen sulfide; β-Secretase; γ-Secretase