title: Low levels of copper disrupt brain amyloid-β homeostasis by altering its production and clearance.
abstract: Whereas amyloid-β (Aβ) accumulates in the brain of normal animals dosed with low levels of copper (Cu), the mechanism is not completely known. Cu could contribute to Aβ accumulation by altering its clearance and/or its production. Because Cu homeostasis is altered in transgenic mice overexpressing Aβ precursor protein (APP), the objective of this study was to elucidate the mechanism of Cu-induced Aβ accumulation in brains of normal mice and then to explore Cu's effects in a mouse model of Alzheimer's disease. In aging mice, accumulation of Cu in brain capillaries was associated with its reduction in low-density lipoprotein receptor-related protein 1 (LRP1), an Aβ transporter, and higher brain Aβ levels. These effects were reproduced by chronic dosing with low levels of Cu via drinking water without changes in Aβ synthesis or degradation. In human brain endothelial cells, Cu, at its normal labile levels, caused LRP1-specific down-regulation by inducing its nitrotyrosination and subsequent proteosomal-dependent degradation due in part to Cu/cellular prion protein/LRP1 interaction. In APP(sw/0) mice, Cu not only down-regulated LRP1 in brain capillaries but also increased Aβ production and neuroinflammation because Cu accumulated in brain capillaries and, unlike in control mice, in the parenchyma. Thus, we have demonstrated that Cu's effect on brain Aβ homeostasis depends on whether it is accumulated in the capillaries or in the parenchyma. These findings should provide unique insights into preventative and/or therapeutic approaches to control neurotoxic Aβ levels in the aging brain.
authors: Department of Neurosurgery, University of Rochester Medical Center, Rochester NY 14642, USA.
authors: Itender
authors: I
authors: Singh
authors: Abhay P
authors: AP
authors: Sagare
authors: Mireia
authors: M
authors: Coma
authors: David
authors: D
authors: Perlmutter
authors: Robert
authors: R
authors: Gelein
authors: Robert D
authors: RD
authors: Bell
authors: Richard J
authors: RJ
authors: Deane
authors: Elaine
authors: E
authors: Zhong
authors: Margaret
authors: M
authors: Parisi
authors: Joseph
authors: J
authors: Ciszewski
authors: R Tristan
authors: RT
authors: Kasper
authors: Rashid
authors: R
authors: Deane
mesh_terms: D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000493:pharmacokinetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007457:Iodine Radioisotopes; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D003300:Copper
keywords: BACE1; BBB; cerebrovascular; environmental; toxicity
references: Neurotherapeutics. 2008 Jul;5(3):421-32
references: 18625454
references: Am J Clin Nutr. 2008 Sep;88(3):826S-9S
references: 18779302
references: J Alzheimers Dis. 2010;20(2):509-16
references: 20164561
references: J Alzheimers Dis. 2005 Nov;8(2):201-6; discussion 209-15
references: 16308488
references: J Clin Invest. 2008 Dec;118(12):4002-13
references: 19033669
references: J Neurochem. 1990 Mar;54(3):905-14
references: 2106011
references: Brain Res. 2009 Jan 12;1248:14-21
references: 19014916
references: Biochemistry. 2004 Jan 20;43(2):560-8
references: 14717612
references: J Trace Elem Med Biol. 2012 Jun;26(2-3):93-6
references: 22565015
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14193-8
references: 14617772
references: Biofactors. 2012 Mar-Apr;38(2):107-13
references: 22438177
references: J Biol Chem. 2004 Apr 30;279(18):18169-77
references: 14978032
references: J Neurosci. 1997 Apr 15;17(8):2653-7
references: 9092586
references: Prog Neurobiol. 2005 Jun;76(2):126-52
references: 16115721
references: Free Radic Biol Med. 2012 Jan 15;52(2):298-302
references: 22080049
references: Neurobiol Dis. 2006 Apr;22(1):76-87
references: 16378731
references: J Neurochem. 2004 Feb;88(4):813-20
references: 14756801
references: Lancet Neurol. 2008 Sep;7(9):779-86
references: 18672400
references: Am J Med Sci. 1986 Dec;292(6):344-9
references: 3799705
references: Acta Neuropathol. 2006 Oct;112(4):405-15
references: 16865397
references: Proc Soc Exp Biol Med. 1978 May;158(1):113-6
references: 662866
references: Neurology. 2002 Oct 22;59(8):1153-61
references: 12391342
references: J Biol Chem. 1999 Dec 24;274(52):37111-6
references: 10601271
references: Am J Physiol. 1985 Jul;249(1 Pt 1):E77-88
references: 3925789
references: Proc Natl Acad Sci U S A. 2012 Jan 31;109(5):1737-42
references: 22307640
references: Neuron. 2008 Jan 24;57(2):178-201
references: 18215617
references: J Cell Biochem. 1998 Jun 1;69(3):326-35
references: 9581871
references: J Neurochem. 2011 Jul;118(1):105-12
references: 21517843
references: J Nutr Health Aging. 2006 Jul-Aug;10(4):247-54
references: 16886094
references: Sci Transl Med. 2012 Aug 15;4(147):147ra111
references: 22896675
references: J Biol Chem. 2002 Nov 22;277(47):44670-6
references: 12215434
references: J Alzheimers Dis. 2004 Jun;6(3):291-301
references: 15201484
references: Neuron. 2001 Oct 25;32(2):177-80
references: 11683988
references: Biochemistry. 1998 May 19;37(20):7185-93
references: 9585530
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11065-9
references: 12920183
references: J Neurol Sci. 1998 Jun 11;158(1):47-52
references: 9667777
references: J Neurochem. 1999 Sep;73(3):1288-92
references: 10461923
references: Annu Rev Nutr. 2000;20:291-310
references: 10940336
references: Eur Biophys J. 2008 Mar;37(3):269-79
references: 18030462
references: J Neurochem. 2011 Oct;119(1):220-30
references: 21797865
references: Metallomics. 2010 Sep;2(9):596-608
references: 21072351
references: Nat Med. 2005 Sep;11(9):959-65
references: 16116430
references: Brain. 2005 Jul;128(Pt 7):1613-21
references: 15817516
references: Biochem J. 2007 Feb 15;402(1):17-23
references: 17155929
references: J Neurochem. 1989 Sep;53(3):817-24
references: 2760621
references: Neurology. 2006 Jul 11;67(1):76-82
references: 16832081
references: J Clin Invest. 2012 Apr;122(4):1377-92
references: 22406537
references: J Biol Chem. 2011 Mar 18;286(11):9776-86
references: 21239495
references: Neuron. 2004 Aug 5;43(3):333-44
references: 15294142
references: Sci Rep. 2011;1:11
references: 22355530
references: J Natl Cancer Inst. 1985 Aug;75(2):277-84
references: 3860683
references: Curr Alzheimer Res. 2007 Apr;4(2):191-7
references: 17430246
references: Ann N Y Acad Sci. 1994 Nov 17;738:447-54
references: 7832455
references: J Nutr. 1998 Aug;128(8):1276-82
references: 9687544
references: Pharmacol Ther. 2005 Nov;108(2):129-48
references: 16112736
references: Mol Neurobiol. 2001 Feb;23(1):53-67
references: 11642543
references: J Am Coll Nutr. 2009 Jun;28(3):238-42
references: 20150596
references: Chem Res Toxicol. 2003 Apr;16(4):531-5
references: 12703970
references: Biochem J. 1999 Dec 1;344 Pt 2:461-7
references: 10567229
references: J Biol Chem. 2009 Aug 14;284(33):21899-21907
references: 19542222
references: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14187-92
references: 14617773
references: CNS Neurol Disord Drug Targets. 2009 Mar;8(1):16-30
references: 19275634
references: Am J Clin Nutr. 1998 May;67(5 Suppl):1054S-1060S
references: 9587151
references: Free Radic Biol Med. 2002 Jun 1;32(11):1050-60
references: 12031889