Humanin protects neurons against apoptosis induced by Aβ31-35 through suppression of intrinsic pathway

( views:93, downloads:0 )
Author:
LI Ling-Min(Department of Pathology,Shanxi Medical University,Taiyuan 030001,China)
ZHANG Yu(Department of Physiology,Shanxi Medical University,Taiyuan 030001,China)
QIAO Jian-Tian(Department of Physiology,Shanxi Medical University,Taiyuan 030001,China)
ZHANG Ce(Department of Physiology,Shanxi Medical University,Taiyuan 030001,China)
Journal Title:
ACTA PHYSIOLOGICA SINICA
Issue:
Volume 62, Issue 02, 2010
DOI:
Key Word:
Aβ31-35;humanin;apoptosis;neuroprotection;intrinsic pathways

Abstract: The present study aimed to investigate the effects of humanin (HN) on primary cortical neuronal apoptosis induced by Aβ31-35, and explore the potential mechanisms. Cultured cortical neurons were pretreated with different concentrations of HN (5, 10, 20 μmol/L) for different time period (0, 8 and 16 h) respectively, and then exposed to Aβ31-35 (25 μmol/L) for additional 24 h and the neuronal apoptosis was examined by morphological analysis, flow cytometric assays and TUNEL staining. Caspase activities were measured using a spectrophotometer. Bax expression was measured by Western blot. The results were as follows. (1) Pretreatment with HN (20μmol/L) for 16 h significantly prevented Aβ31-35-induced apoptosis in cortical neurons; (2) HN significantly decreased Aβ31-35-induced elevation of caspase-3 and -9 activities; (3) HN suppressed Aβ31-35-induced translocation of Bax from the cytosol to mitochondria, but had no effect on overall Bax expression. In conclusions, HN attenuated Aβ31-35-induced cortical neuronal apoptosis by blocking intrinsic caspase-dependent apoptotic pathways.

  • [1]Golde TE.The Abeta hypothesis:leading us to rationallydesigned therapeutic strategies for the treatment or prevention of Alzheimer disease.Brain Pattol 2005; 15(1):84-87.
  • [2]Niikura T,Hashimoto Y,Tajima H,Nishimoto I.Death and survival of neuronal cells exposed to Alzheimer's insults.Neurosci Res 2002; 70(3):380-391.
  • [3]Yankner BA,Duffy LK,Kirschner DA.Neurotrophic and neurotoxic effects of amyloid β protein:reversal by tachykinin neuropeptides.Science 1990; 250(4978):279-282.
  • [4]Allen JW,Eldadah BA,Huang X,Knoblach SM,Faden AI.Multiple caspases are involved in beta-amyloid-induced neuronal apoptosis.Neurosci Res 2001; 65(1):45-53.
  • [5]Matsui T,Ramasamy K,Ingelsson M,Fukumoto H,Conrad C,Frosch MP,Irizarry MC,Yuan J,Hyman BT.Coordinated expression of caspase 8,3 and 7 mRNA in temporal cortex of Alzheimer disease:relationship to formic acid extractable Abeta42 levels.J Neuropathol Exp Neurol 2006; 65(5):508-515.
  • [6]Wei W,Norton DD,Wang X,Kusiak JW Abeta 17-42 in Alzheimer's disease activates JNK and caspase-8 leading to neuronal apoptosis.Brain 2002; 125(pt9):2036-2043.
  • [7]Qi JS,Ye L,Qiao JT.Amyloid β-protein fragment 31-35suppresses delayed rectifying potassium channels in membrane patches excised from hippocampal neurons in rats.Synapse 2004;51:165-172.
  • [8]Yan XZ,Qiao JT,Dou Y,Qiao ZD.β-amyloid fragment 31-35induces apoptosis in cultured cortical neurons.Neuroscience1999; 92(1):177-184.
  • [9]Zhao L,Qian ZM,Zhang C,Wing HY,Du F,Ya K.Amyloid β-peptide 31-35-induced neuronal apoptosis is mediated by caspasedependent pathways via cAMP-dependent protein kinase activation.Aging Cell 2008; 7(1):47-57.
  • [10]HashimotoY,Niikura T,ItoY,Nishimoto I.Multiple mechanisms underlie neurotoxicity by different types of Alzheimer's disease mutations of amyloid precursor protein.Biol Chem 2000;275(44):34541-34551.
  • [11]Hashimoto Y,Ito Y,Niikura T,Shao Z,Hata M,Oyama F,Nishimoto I.Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein.Biochem Biophys Res Commun 2001; 283(2):460-468.
  • [12]Hashimoto Y,Niikura T,Ito Y,Sudo H,Hata M,Arakawa E,Abe Y,Kita Y,Nishimoto I.Detailed characterization of neuroprotection by a rescue factor humanin against various Alzheimer's disease-relevant insults.J Neurosci 2002; 21(23):9235-9245.
  • [13]Hashimoto Y,Ito Y,Arakawa E,Kita Y,Terashita K,Niikura T,Nishimoto I.Neurotoxic mechanisms triggered by Alzheimer's disease-linked mutant M 146L presenilin 1:involvement of NO synthase via a novel pertussis toxin target.Neurochem 2002; 80(3):426-437.
  • [14]Guo B,Zhai D,Cabezas E,Welsh K,Nouraini S,Satterthwait AC,Reed JC.Humanin peptide suppresses apoptosis by interfering with Bax activation.Nature 2003; 423(6938):456-461.
  • [15]Ho KP,Li L,Zhao L,Qian ZM.Genistein protects primary cortical neurons from iron-induced lipid peroxidation.Mol Cell Biochem 2003; 247(1-2):219-222.
  • [16]Zhang X,Li B,Zhang Y,Liu J.Ceramide induces release of mitochondrial proapoptotic proteins in caspase-dependent and-independent manner in HT-29 cells.Sci China C Life Sci 2008;51(1):66-71.
  • [17]Ying G,Iribarren P,Zhou Y,Gong W,Zhang N,Yu ZX,Le Y,Cui Y,Wang JM.Humanin,a newly identified neuroprotective factor,uses the G protein-coupled formylpeptide receptor-like1 as a functional receptor.J Immunol 2004; 172(11):7078-7085.
  • [18]Li LM(李灵敏),Qiao JT,Zhang C.Effects of humanin on elevation of intracellular calcium concentration induced by β-amyloid peptide 31-35 in cultured cortical neurons.Acta Physiol Sin(生理学报)2009; 61(2):127-131(Chinese,English abstract).
  • [19]Castedo M,Prefettini J,Andreau K,Roumier T,Piacentini M,Kroemer G.Mitochondrial apoptosis induced by the HIV-1envelope.Ann N Y Acad Sci 2003; 12(1010):19-28.
  • [20]Cervais FG,Xu D,Robertson GS,Vaillancourt JP,Zhu Y,Huang J,LeBlanc A,Smith D,Rigby M,Shearman MS,Clarke EE,Zheng H,Van Der Ploeg LH,Ruffolo SC,Thornberry NA,Xanthoudakis S,Zamboni RJ,Roy S,Nicholson DW.Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic Abeta peptide formation.Cell 1999;97(3):395-406.
  • [21]Janicke RU,Sprengart ML,Wati MR,Porter AG.Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis.Biol Chem 1998; 273(16):9357-9360.
  • [22]Desagher S,Martinou JC.Mitochondria as the central control point of apoptosis.Trends Cell Biol 2000; 10(9):369-377.
  • [23]Clementi ME,Pezzotti M,Orsini F,Sampaolese B,Mezzogori D,GrassiC,Giardina B,Misiti F.Alzheimer's amyloid betapeptide(1-42)induces cell death in human neuroblastoma via bax/bcl-2 ratio increase:an intriguing role for methionine 35.Biochem Biophys Res Commun 2006; 342(1):206-213.
  • [24]Yu HL,Li L,Zhang XH,Xiang L,Zhang J,Feng JF,Xiao R.Neuroprotective effects of genistein and folic acid on apoptosis of rat cultured cortical neurons induced by beta-amyloid 31-35.Br J Nutr 2009; 102(5):655-662.
  • [25]Paradis E,Douillard H,Koutroumanis M,Goodyer C,LeBlanc A.Amyloid beta peptide of Alzheimer's disease downregulates Bcl-2 and upregulates bax expression in human neurons.J Neurosci 1996; 16(23):7533-7539.
  • [26]Jang MH,Jung SB,Lee MH,Kim CI,Oh YT,Kang I,Kim J,Kim EH.Melatonin attenuates amyloid beta25-35-induced apoptosis in mouse microgliai BV2 cells.Nenrosci Lett 2005; 380(1-2):2631.
  • [27]Wei Z,Mousseau DD,Richardson JS,Dyck LE,Li XM.Typical antipsychotics attenuate neurotoxicity of beta-amyloid(2535)by modulating Bax and Bcl-X(l/s)expression and localization.Neurosci Res 2003; 74(6):942-947.
WanfangData CO.,Ltd All Rights Reserved
About WanfangData | Contact US
Healthcare Department, Fuxing Road NO.15, Haidian District Beijing, 100038 P.R.China
Tel:+86-010-58882616 Fax:+86-010-58882615 Email:yiyao@wanfangdata.com.cn