title: Hypoxia-triggered m-calpain activation evokes endoplasmic reticulum stress and neuropathogenesis in a transgenic mouse model of Alzheimer's disease.
abstract: BACKGROUND
  Previous studies have demonstrated that endoplasmic reticulum (ER) stress is activated in Alzheimer's disease (AD) brains. ER stress-triggered unfolded protein response (UPR) leads to tau phosphorylation and neuronal death.
  
  
  OBJECTIVE
  In this study, we tested the hypothesis that hypoxia-induced m-calpain activation is involved in ER stress-mediated AD pathogenesis.
  
  
  METHODS
  We employed a hypoxic exposure in APP/PS1 transgenic mice and SH-SY5Y cells overexpressing human Swedish mutation APP (APPswe).
  
  
  RESULTS
  We observed that hypoxia impaired spatial learning and memory in the APP/PS1 mouse. In the transgenic mouse brain, hypoxia increased the UPR, upregulated apoptotic signaling, enhanced the activation of calpain and glycogen synthase kinase-3β (GSK3β), and increased tau hyperphosphorylation and β-amyloid deposition. In APPswe cells, m-calpain silencing reduced hypoxia-induced cellular dysfunction and resulted in suppression of GSK3β activation, ER stress and tau hyperphosphorylation reduction as well as caspase pathway suppression.
  
  
  CONCLUSIONS
  These findings demonstrate that hypoxia-induced abnormal calpain activation may increase ER stress-induced apoptosis in AD pathogenesis. In contrast, a reduction in the expression of the m-calpain isoform reduces ER stress-linked apoptosis that is triggered by hypoxia. These findings suggest that hypoxia-triggered m-calpain activation is involved in ER stress-mediated AD pathogenesis. m-calpain is a potential target for AD therapeutics.
authors.affiliation: Department of Pathophysiology, Key Laboratory of Medical Cell Biology of Ministry of Education of China, China Medical University, Shenyang, China; Medical Research Laboratory, Jilin Medical College, Jilin, China.
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wang
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xie
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.forename: Jian-Hui
authors.initials: JH
authors.lastname: Cai
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.forename: Bao-Lu
authors.initials: BL
authors.lastname: Zhao
authors.forename: Li
authors.initials: L
authors.lastname: An
authors.forename: Zhan-You
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology / Q000502:physiology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053764:Presenilin-1 / Q000235:genetics; D011897:Random Allocation
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D002154:Calpain; C449000:m-calpain
keywords: APP/PS1 transgenic mouse; Alzheimer's disease; Calpain; Endoplasmic reticulum stress; Glycogen synthase kinase 3; Hypoxia; RNA interference
references.citation: Cell. 2000 Apr 28;101(3):249-58
references.pmid: 10847680
references.citation: Am J Pathol. 2009 Apr;174(4):1241-51
references.pmid: 19264902
references.citation: Curr Alzheimer Res. 2008 Oct;5(5):469-74
references.pmid: 18855588
references.citation: J Neurochem. 2009 Jun;109(5):1324-37
references.pmid: 19476545
references.citation: Neurobiol Aging. 2006 Jul;27(7):973-82
references.pmid: 15964666
references.citation: Ann N Y Acad Sci. 2000;924:117-31
references.pmid: 11193788
references.citation: Ann N Y Acad Sci. 2003 Dec;1010:186-94
references.pmid: 15033718
references.citation: Apoptosis. 2007 Apr;12(4):707-18
references.pmid: 17195093
references.citation: Lancet Neurol. 2003 Oct;2(10):605-13
references.pmid: 14505582
references.citation: J Neurosci. 2008 Nov 19;28(47):12241-54
references.pmid: 19020018
references.citation: Physiol Rev. 2003 Jul;83(3):731-801
references.pmid: 12843408
references.citation: J Neurochem. 2002 Nov;83(3):673-81
references.pmid: 12390529
references.citation: EMBO J. 2001 Jan 15;20(1-2):27-39
references.pmid: 11226152
references.citation: Neurol Res. 2006 Sep;28(6):605-11
references.pmid: 16945211
references.citation: Trends Mol Med. 2004 Sep;10(9):452-8
references.pmid: 15350898
references.citation: Neurosignals. 2005;14(5):255-61
references.pmid: 16301840
references.citation: Mol Neurobiol. 2002 Oct-Dec;26(2-3):283-98
references.pmid: 12428761
references.citation: Cell. 2000 May 26;101(5):451-4
references.pmid: 10850487
references.citation: Neurobiol Aging. 2005 Mar;26(3):325-34
references.pmid: 15639310
references.citation: IUBMB Life. 2009 May;61(5):516-21
references.pmid: 19391164
references.citation: PLoS One. 2010 Dec 17;5(12):e15349
references.pmid: 21179415
references.citation: Oncogene. 1998 Sep 3;17(9):1069-78
references.pmid: 9764817
references.citation: J Neurosci Res. 2006 Feb 15;83(3):374-84
references.pmid: 16385556
references.citation: Methods Mol Biol. 2009;559:191-204
references.pmid: 19609758
references.citation: Neuron. 2001 Jan;29(1):15-32
references.pmid: 11182078
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Neurobiol Aging. 2013 Mar;34(3):663-78
references.pmid: 22795785
references.citation: Nature. 2003 May 22;423(6938):435-9
references.pmid: 12761548
references.citation: J Cell Biochem. 2000 Apr;78(1):151-9
references.pmid: 10797574
references.citation: Mol Chem Neuropathol. 1996 Oct-Dec;29(2-3):253-61
references.pmid: 8971700
references.citation: J Alzheimers Dis. 1999 Nov;1(4-5):329-51
references.pmid: 12214129
references.citation: Neurobiol Aging. 2003 Jan-Feb;24(1):179-86
references.pmid: 12493564
references.citation: Nature. 2000 May 18;405(6784):360-4
references.pmid: 10830966
references.citation: J Biol Chem. 2007 Oct 26;282(43):31675-87
references.pmid: 17785458
references.citation: Neuropsychopharmacology. 2011 Apr;36(5):1073-89
references.pmid: 21289607
references.citation: Curr Opin Cell Biol. 2006 Aug;18(4):444-52
references.pmid: 16781856
references.citation: J Neurochem. 2011 May;117(3):504-15
references.pmid: 21338355
references.citation: Traffic. 2001 Aug;2(8):515-23
references.pmid: 11489209
references.citation: J Biol Chem. 2010 Sep 3;285(36):27737-44
references.pmid: 20595388
references.citation: J Mol Neurosci. 2013 Sep;51(1):138-47
references.pmid: 23345083
references.citation: Am J Pathol. 2003 Sep;163(3):1057-67
references.pmid: 12937146
references.citation: Physiol Rev. 2005 Jan;85(1):201-79
references.pmid: 15618481
references.citation: PLoS One. 2010 May 05;5(5):e10489
references.pmid: 20463975
references.citation: Curr Alzheimer Res. 2010 Dec;7(8):656-64
references.pmid: 20678074
references.citation: Proc Natl Acad Sci U S A. 2006 Dec 5;103(49):18727-32
references.pmid: 17121991
references.citation: Neurobiol Aging. 2009 Jul;30(7):1091-8
references.pmid: 18063223
references.citation: Prog Neurobiol. 2001 Nov;65(4):391-426
references.pmid: 11527574
references.citation: Ann N Y Acad Sci. 1989;568:1-4
references.pmid: 2629579
references.citation: Trends Neurosci. 2003 Aug;26(8):407-10
references.pmid: 12900170
references.citation: Nature. 2000 Jan 6;403(6765):98-103
references.pmid: 10638761
references.citation: Nat Rev Mol Cell Biol. 2003 Jul;4(7):552-65
references.pmid: 12838338
references.citation: Biochim Biophys Acta. 2011 Apr;1812(4):549-57
references.pmid: 20804843
references.citation: Trends Cell Biol. 2004 Jan;14(1):20-8
references.pmid: 14729177
references.citation: Toxicol Sci. 2006 Nov;94(1):118-28
references.pmid: 16920763
references.citation: Nat Rev Neurosci. 2002 Nov;3(11):862-72
references.pmid: 12415294
references.citation: J Cell Biol. 2000 Aug 21;150(4):887-94
references.pmid: 10953012
references.citation: Acta Neuropathol. 2005 Aug;110(2):165-72
references.pmid: 15973543
references.citation: EMBO J. 2001 Jun 1;20(11):2702-14
references.pmid: 11387205
references.citation: Brain. 2010 Mar;133(Pt 3):808-21
references.pmid: 20123724
references.citation: Cell Death Differ. 2004 Apr;11(4):381-9
references.pmid: 14685163
references.citation: Int J Biochem Cell Biol. 2013 Jul;45(7):1377-88
references.pmid: 23603149
references.citation: Nat Rev Mol Cell Biol. 2007 Jul;8(7):519-29
references.pmid: 17565364
references.citation: J Biol Chem. 2002 Nov 22;277(47):44701-8
references.pmid: 12228224
references.citation: J Biol Chem. 2007 Aug 3;282(31):22406-13
references.pmid: 17569662
references.citation: J Neuropathol Exp Neurol. 2006 Apr;65(4):348-57
references.pmid: 16691116
references.citation: Oncogene. 2003 Nov 24;22(53):8608-18
references.pmid: 14634622
references.citation: J Exp Med. 2008 Nov 24;205(12):2781-9
references.pmid: 18955571
references.citation: Trends Neurosci. 2000 Feb;23(2):59
references.pmid: 10652545
references.citation: Nature. 1995 Dec 21-28;378(6559):785-9
references.pmid: 8524413
references.citation: J Biol Chem. 2001 Nov 30;276(48):44736-43
references.pmid: 11574534
references.citation: Brain Res. 1996 Oct 21;737(1-2):119-32
references.pmid: 8930358
references.citation: FASEB J. 1995 Dec;9(15):1570-6
references.pmid: 8529836
references.citation: Neurology. 2006 Jan 24;66(2 Suppl 1):S102-9
references.pmid: 16432136
references.citation: J Biol Chem. 2006 Sep 1;281(35):25457-65
references.pmid: 16803897
references.citation: Neurobiol Aging. 2012 Jun;33(6):1125.e9-18
references.pmid: 22206846