title: PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain.
abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates hepatic low-density lipoprotein receptor (LDLR) levels in humans. PCSK9 has also been shown to regulate the levels of additional membrane-bound proteins in vitro, including the very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 (ApoER2) and the beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which are all highly expressed in the CNS and have been implicated in Alzheimer's disease. To better understand the role of PCSK9 in regulating these additional target proteins in vivo, their steady-state levels were measured in the brain of wild-type, PCSK9-deficient, and human PCSK9 overexpressing transgenic mice. We found that while PCSK9 directly bound to recombinant LDLR, VLDLR, and apoER2 protein in vitro, changes in PCSK9 expression did not alter the level of these receptors in the mouse brain. In addition, we found no evidence that PCSK9 regulates BACE1 levels or APP processing in the mouse brain. In conclusion, our results suggest that while PCSK9 plays an important role in regulating circulating LDL cholesterol levels by reducing the number of hepatic LDLRs, it does not appear to modulate the levels of LDLR and other membrane-bound proteins in the adult mouse brain.
authors.affiliation: Neurology Department, Merck Research Laboratories, West Point, PA, USA.
authors.forename: Mali
authors.initials: M
authors.lastname: Liu
authors.forename: Guoxin
authors.initials: G
authors.lastname: Wu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Baysarowich
authors.forename: Michael
authors.initials: M
authors.lastname: Kavana
authors.forename: George H
authors.initials: GH
authors.lastname: Addona
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Bierilo
authors.forename: John S
authors.initials: JS
authors.lastname: Mudgett
authors.forename: Guillaume
authors.initials: G
authors.lastname: Pavlovic
authors.forename: Ayesha
authors.initials: A
authors.lastname: Sitlani
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Brian K
authors.initials: BK
authors.lastname: Hubbard
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Fisher
authors.forename: Celina V
authors.initials: CV
authors.lastname: Zerbinatti
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D011485:Protein Binding; D011973:Receptors, LDL / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D026502:LDL-Receptor Related Proteins; D011973:Receptors, LDL; C036053:VLDL receptor; C098773:low density lipoprotein receptor-related protein 8; D053829:Amyloid Precursor Protein Secretases; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse
references.citation: J Lipid Res. 2008 Jun;49(6):1303-11
references.pmid: 18354138
references.citation: Proc Natl Acad Sci U S A. 2005 Apr 12;102(15):5374-9
references.pmid: 15805190
references.citation: Nat Genet. 2005 Feb;37(2):161-5
references.pmid: 15654334
references.citation: Biochem J. 2009 May 1;419(3):577-84
references.pmid: 19196236
references.citation: Proc Natl Acad Sci U S A. 2004 May 4;101(18):7100-5
references.pmid: 15118091
references.citation: Biochem Biophys Res Commun. 2008 Oct 10;375(1):69-73
references.pmid: 18675252
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 16;106(24):9820-5
references.pmid: 19443683
references.citation: J Biol Chem. 1996 Apr 5;271(14):8373-80
references.pmid: 8626535
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):928-33
references.pmid: 12552133
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 19;105(33):11915-20
references.pmid: 18695239
references.citation: EMBO Rep. 2008 Sep;9(9):916-22
references.pmid: 18660751
references.citation: J Biol Chem. 2008 Jan 25;283(4):2363-72
references.pmid: 18039658
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2069-74
references.pmid: 15677715
references.citation: J Biol Chem. 2007 Jun 22;282(25):18602-18612
references.pmid: 17452316
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81
references.pmid: 8446617
references.citation: Nat Rev Neurosci. 2006 Nov;7(11):850-9
references.pmid: 17053810
references.citation: Neuron. 2007 Oct 4;56(1):66-78
references.pmid: 17920016
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15938-43
references.pmid: 19805234
references.citation: Science. 1999 Oct 22;286(5440):735-41
references.pmid: 10531052
references.citation: N Engl J Med. 2006 Mar 23;354(12):1264-72
references.pmid: 16554528
references.citation: J Biol Chem. 2002 Oct 18;277(42):39944-52
references.pmid: 12167620
references.citation: Nat Genet. 2003 Jun;34(2):154-6
references.pmid: 12730697
references.citation: J Clin Invest. 2006 Nov;116(11):2995-3005
references.pmid: 17080197
references.citation: Nat Struct Mol Biol. 2007 May;14(5):413-9
references.pmid: 17435765
references.citation: Hum Mutat. 2009 Apr;30(4):520-9
references.pmid: 19191301
references.citation: Neuron. 2009 Dec 10;64(5):632-44
references.pmid: 20005821
references.citation: Trends Biochem Sci. 2007 Feb;32(2):71-7
references.pmid: 17215125
references.citation: Biochem Biophys Res Commun. 2008 Jun 13;370(4):634-40
references.pmid: 18406350
references.citation: J Biol Chem. 2009 Jan 9;284(2):1313-23
references.pmid: 19001363
references.citation: Curr Opin Lipidol. 2009 Jun;20(3):190-6
references.pmid: 19433918
references.citation: Clin Genet. 2004 May;65(5):419-22
references.pmid: 15099351
references.citation: Nat Rev Neurosci. 2009 May;10(5):333-44
references.pmid: 19339974
references.citation: J Biol Chem. 2005 Jul 8;280(27):25754-9
references.pmid: 15888448
references.citation: Endocrinology. 1994 Jul;135(1):387-94
references.pmid: 8013374
references.citation: Neurosci Lett. 2004 Sep 23;368(2):144-7
references.pmid: 15351437
references.citation: J Neurosci. 2007 Mar 14;27(11):2727-33
references.pmid: 17360894
references.citation: Science. 2009 Jul 3;325(5936):100-4
references.pmid: 19520913
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1820-5
references.pmid: 18250299
references.citation: J Biol Chem. 2007 Jul 13;282(28):20502-12
references.pmid: 17493938
references.citation: J Lipid Res. 2007 Apr;48(4):763-7
references.pmid: 17242417
references.citation: J Lipid Res. 2008 Jun;49(6):1333-43
references.pmid: 18354137
references.citation: J Biol Chem. 2004 Nov 26;279(48):50630-8
references.pmid: 15385538