title: Trientine reduces BACE1 activity and mitigates amyloidosis via the AGE/RAGE/NF-κB pathway in a transgenic mouse model of Alzheimer's disease.
abstract: OBJECTIVE
  There is mounting evidence that the transition metal copper may play an important role in the pathophysiology of Alzheimer's disease (AD). Triethylene tetramine dihydrochloride (trientine), a CuII-selective chelator, is a commonly used treatment for Wilson's disease to decrease accumulated copper, and thereby decreases oxidative stress. In the present study, we evaluated the effects of a 3-month treatment course of trientine (Trien) on amyloidosis in 7-month-old β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1) double transgenic (Tg) AD model mice.
  
  
  RESULTS
  We observed that Trien reduced the level of advanced glycation end products (AGEs), and decreased Aβ deposition and synapse loss in brain of APP/PS1 mice. Importantly, we found that Trien blocked the receptor for AGEs (RAGE), downregulated β-site APP cleaving enzyme 1 (BACE1), inhibited amyloidogenic APP cleavage, and subsequently reduced Aβ levels. In vitro, in SH-SY5Y cells overexpressing Swedish mutant APP, Trien-mediated downregulation of BACE1 occurred via inhibition of the NF-κB signaling pathway.
  
  
  METHODS
  In this study, we demonstrated for the first time that Trien inhibited amyloidogenic pathway including targeting the downregulation of RAGE and NF-κB.
  
  
  CONCLUSIONS
  Trien might mitigate amyloidosis in AD by inhibiting the RAGE/NF-κB/BACE1 pathway. Our study demonstrates that Trien may be a viable therapeutic strategy for the intervention and treatment of AD and other AD-like pathologies.
authors.affiliation: 1 Key Laboratory of Medical Cell Biology of Ministry of Education of China, Department of Pathophysiology, China Medical University , Shenyang, People's Republic of China .
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Wang
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Xie
authors.forename: Ye
authors.initials: Y
authors.lastname: Xu
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
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 / Q000097:blood / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000686:Amyloidosis / Q000201:enzymology* / Q000517:prevention & control; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D002570:Ceruloplasmin / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003300:Copper / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014266:Trientine / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D002614:Chelating Agents; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C000606290:SOD1 protein, human; D008315:Malondialdehyde; D003300:Copper; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002570:Ceruloplasmin; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D014266:Trientine
references.citation: Neuron. 2001 Jun;30(3):665-76
references.pmid: 11430801
references.citation: Biochemistry. 2004 Jan 20;43(2):560-8
references.pmid: 14717612
references.citation: J Biol Chem. 1994 Apr 22;269(16):12152-8
references.pmid: 8163520
references.citation: Diabetes Metab Res Rev. 2002 Sep-Oct;18(5):395-402
references.pmid: 12397582
references.citation: Neurobiol Aging. 2012 Jan;33(1):196.e13-27
references.pmid: 20638753
references.citation: Lancet. 1982 Mar 20;1(8273):643-7
references.pmid: 6121964
references.citation: Mol Aspects Med. 2011 Aug;32(4-6):279-304
references.pmid: 22020114
references.citation: Diabetologia. 2009 Apr;52(4):715-22
references.pmid: 19172243
references.citation: Cell. 1989 Aug 25;58(4):611-2
references.pmid: 2504495
references.citation: J Alzheimers Dis. 2009;16(4):809-21
references.pmid: 19387114
references.citation: J Neurochem. 2006 Jan;96(1):1-13
references.pmid: 16305625
references.citation: Science. 2002 Oct 25;298(5594):789-91
references.pmid: 12399581
references.citation: Biochemistry. 2012 Aug 14;51(32):6289-311
references.pmid: 22708607
references.citation: J Biol Chem. 1994 Apr 1;269(13):9889-97
references.pmid: 8144582
references.citation: Biomed Pharmacother. 2008 Sep;62(7):480-5
references.pmid: 18164582
references.citation: J Neurosci Res. 2007 May 1;85(6):1194-204
references.pmid: 17385716
references.citation: J Alzheimers Dis. 2010;21(3):903-14
references.pmid: 20693639
references.citation: Alzheimer Dis Assoc Disord. 2003 Jul-Sep;17(3):147-50
references.pmid: 14512827
references.citation: Int J Cancer. 2002 Dec 10;102(5):445-52
references.pmid: 12432545
references.citation: Biochemistry. 2003 Mar 18;42(10):2768-73
references.pmid: 12627941
references.citation: J Struct Biol. 2000 Jun;130(2-3):209-16
references.pmid: 10940226
references.citation: J Biol Chem. 2008 Apr 11;283(15):10037-47
references.pmid: 18263584
references.citation: Brain Res. 2008 Sep 16;1230:273-80
references.pmid: 18657529
references.citation: Neurology. 2006 Jul 11;67(1):69-75
references.pmid: 16832080
references.citation: Diabetes. 2004 Feb;53(2):474-81
references.pmid: 14747300
references.citation: Science. 2002 Jul 19;297(5580):353-6
references.pmid: 12130773
references.citation: Science. 1992 Apr 10;256(5054):184-5
references.pmid: 1566067
references.citation: Free Radic Biol Med. 1997;23(1):134-47
references.pmid: 9165306
references.citation: EMBO J. 2004 Oct 13;23(20):4096-105
references.pmid: 15457210
references.citation: J Neurosci. 1999 Jun 1;19(11):RC10
references.pmid: 10341271
references.citation: J Clin Invest. 2001 Oct;108(7):949-55
references.pmid: 11581294
references.citation: Stroke. 2004 Nov;35(11 Suppl 1):2628-31
references.pmid: 15459432
references.citation: Nat Med. 2008 Aug;14(8):837-42
references.pmid: 18568035
references.citation: J Biol Chem. 2005 May 6;280(18):17930-7
references.pmid: 15722349
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: Neuropsychopharmacology. 2011 Apr;36(5):1073-89
references.pmid: 21289607
references.citation: J Neurol Sci. 1998 Jun 11;158(1):47-52
references.pmid: 9667777
references.citation: Arch Neurol. 1971 Jul;25(1):28-32
references.pmid: 5146408
references.citation: J Clin Invest. 1995 Aug;96(2):1159-63
references.pmid: 7635953
references.citation: Biochim Biophys Acta. 1997 Feb 27;1360(1):17-29
references.pmid: 9061036
references.citation: Science. 1992 Oct 2;258(5079):126-9
references.pmid: 1439760
references.citation: Am J Epidemiol. 2001 Oct 1;154(7):635-41
references.pmid: 11581097
references.citation: Nat Med. 2003 Jul;9(7):907-13
references.pmid: 12808450
references.citation: J Biol Chem. 2002 Oct 25;277(43):40302-8
references.pmid: 12192006
references.citation: J Biol Chem. 1997 Jul 11;272(28):17810-4
references.pmid: 9211935
references.citation: Biochem Biophys Res Commun. 1998 Apr 7;245(1):161-5
references.pmid: 9535801
references.citation: Brain Res. 1996 Sep 30;735(1):159-68
references.pmid: 8905182
references.citation: Arch Biochem Biophys. 2007 Jul 15;463(2):134-48
references.pmid: 17562324
references.citation: Physiol Rev. 2001 Apr;81(2):741-66
references.pmid: 11274343
references.citation: Exp Neurol. 2001 Sep;171(1):29-45
references.pmid: 11520119
references.citation: J Neural Transm Suppl. 2007;(72):217-33
references.pmid: 17982898
references.citation: Int J Exp Pathol. 2005 Jun;86(3):147-59
references.pmid: 15910549
references.citation: Proteomics. 2001 Dec;1(12):1519-28
references.pmid: 11747211
references.citation: Nature. 1996 Aug 22;382(6593):685-91
references.pmid: 8751438
references.citation: Clin Chem. 1974 Dec;20(12):1556-63
references.pmid: 4214636
references.citation: Genes Dev. 2004 Sep 15;18(18):2195-224
references.pmid: 15371334
references.citation: Curr Alzheimer Res. 2012 Jan;9(1):128-37
references.pmid: 21592054
references.citation: Eur J Pharm Biopharm. 2005 Feb;59(2):263-72
references.pmid: 15661498
references.citation: Nat Rev Neurosci. 2007 Oct;8(10):766-75
references.pmid: 17882254
references.citation: Diabetes. 2004 Sep;53(9):2501-8
references.pmid: 15331567
references.citation: Antioxid Redox Signal. 2011 Nov 1;15(9):2605-41
references.pmid: 21391902
references.citation: Drugs. 2011 Jul 9;71(10):1281-320
references.pmid: 21770477
references.citation: J Inorg Biochem. 2006 May;100(5-6):952-62
references.pmid: 16574231
references.citation: FASEB J. 2009 Aug;23(8):2639-49
references.pmid: 19332646
references.citation: Histochemistry. 1984;81(4):331-5
references.pmid: 6511487
references.citation: Cell Mol Life Sci. 2002 Jul;59(7):1117-28
references.pmid: 12222959
references.citation: Eur J Biochem. 2000 Jul;267(13):4171-8
references.pmid: 10866821
references.citation: Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13313-8
references.pmid: 17686982
references.citation: J Neurosci Methods. 1987 Jun;20(2):91-103
references.pmid: 3600033
references.citation: J Neurosci. 2009 Oct 14;29(41):12787-94
references.pmid: 19828790
references.citation: Free Radic Biol Med. 1995 Feb;18(2):265-9
references.pmid: 7744310
references.citation: Antioxid Redox Signal. 2010 Dec 1;13(11):1763-811
references.pmid: 20446769
references.citation: FASEB J. 1995 Dec;9(15):1570-6
references.pmid: 8529836
references.citation: Biochim Biophys Acta. 2012 May;1822(5):753-83
references.pmid: 22108204
references.citation: Biochim Biophys Acta. 2000 Dec 20;1498(2-3):99-111
references.pmid: 11108954
references.citation: Exp Diabetes Res. 2009;2009:696378
references.pmid: 19390595
references.citation: Proc Natl Acad Sci U S A. 1997 Mar 18;94(6):2642-7
references.pmid: 9122249
references.citation: Gut. 1974 Feb;15(2):125-9
references.pmid: 4820637
references.citation: Free Radic Biol Med. 2002 Jun 1;32(11):1050-60
references.pmid: 12031889