title: Degradation of amyloid beta protein by purified myelin basic protein.
abstract: The progressive accumulation of beta-amyloid (Abeta) in senile plaques and in the cerebral vasculature is the hallmark of Alzheimer disease and related disorders. Impaired clearance of Abeta from the brain likely contributes to the prevalent sporadic form of Alzheimer disease. Several major pathways for Abeta clearance include receptor-mediated cellular uptake, blood-brain barrier transport, and direct proteolytic degradation. Myelin basic protein (MBP) is the major structural protein component of myelin and plays a functional role in the formation and maintenance of the myelin sheath. MBP possesses endogenous serine proteinase activity and can undergo autocatalytic cleavage liberating distinct fragments. Recently, we showed that MBP binds Abeta and inhibits Abeta fibril formation (Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2007) J. Biol. Chem. 282, 9952-9961; Hoos, M. D., Ahmed, M., Smith, S. O., and Van Nostrand, W. E. (2009) Biochemistry 48, 4720-4727). Here we show that Abeta40 and Abeta42 peptides are degraded by purified human brain MBP and recombinant human MBP, but not an MBP fragment that lacks autolytic activity. MBP-mediated Abeta degradation is inhibited by serine proteinase inhibitors. Similarly, Cos-1 cells expressing MBP degrade exogenous Abeta40 and Abeta42. In addition, we demonstrate that purified MBP also degrades assembled fibrillar Abeta in vitro. Mass spectrometry analysis identified distinct degradation products generated from Abeta digestion by MBP. Lastly, we demonstrate in situ that purified MBP can degrade parenchymal amyloid plaques as well as cerebral vascular amyloid that form in brain tissue of Abeta precursor protein transgenic mice. Together, these findings indicate that purified MBP possesses Abeta degrading activity in vitro.
authors.affiliation: Department of Neurosurgery, Stony Brook University, Stony Brook, New York 11794-8122, USA.
authors.forename: Mei-Chen
authors.initials: MC
authors.lastname: Liao
authors.forename: Mahiuddin
authors.initials: M
authors.lastname: Ahmed
authors.forename: Steven O
authors.initials: SO
authors.lastname: Smith
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000737:chemistry*; D010446:Peptide Fragments / Q000737:chemistry; D020033:Protein Isoforms; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D004676:Myelin Basic Protein; D010446:Peptide Fragments; D020033:Protein Isoforms; D011994:Recombinant Proteins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
references.citation: J Biol Chem. 2007 Mar 30;282(13):9952-9961
references.pmid: 17259179
references.citation: Science. 2001 May 25;292(5521):1550-2
references.pmid: 11375493
references.citation: Acta Neuropathol. 1995;89(3):199-203
references.pmid: 7538720
references.citation: Biochemistry. 2005 Sep 27;44(38):12905-13
references.pmid: 16171406
references.citation: Biochemistry. 2009 Jun 9;48(22):4720-7
references.pmid: 19385666
references.citation: J Biol Chem. 2001 Dec 21;276(51):47863-8
references.pmid: 11604391
references.citation: Neuron. 2004 Aug 5;43(3):333-44
references.pmid: 15294142
references.citation: J Biol Chem. 2003 Jan 24;278(4):2081-4
references.pmid: 12464614
references.citation: Acta Neuropathol. 1989;78(4):337-47
references.pmid: 2551122
references.citation: J Biol Chem. 1989 Mar 25;264(9):5121-7
references.pmid: 2466844
references.citation: Biochemistry. 2002 Sep 17;41(37):11080-90
references.pmid: 12220172
references.citation: J Cell Biol. 1982 Oct;95(1):242-8
references.pmid: 6183269
references.citation: Biochemistry. 2007 Aug 28;46(34):9805-12
references.pmid: 17676931
references.citation: Biochem Biophys Res Commun. 1994 Dec 30;205(3):1755-61
references.pmid: 7811262
references.citation: J Biol Chem. 1992 Jan 5;267(1):546-54
references.pmid: 1730616
references.citation: Biochemistry. 1999 Aug 31;38(35):11570-6
references.pmid: 10471309
references.citation: J Neurosci Res. 2000 Jan 15;59(2):153-9
references.pmid: 10650873
references.citation: J Biomed Biotechnol. 2006;2006(3):58406
references.pmid: 17047308
references.citation: Arch Neurol. 2003 Mar;60(3):393-8
references.pmid: 12633151
references.citation: J Neurosci. 1996 Dec 15;16(24):7910-9
references.pmid: 8987819
references.citation: Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7
references.pmid: 12634421
references.citation: Nat Med. 2003 Jul;9(7):907-13
references.pmid: 12808450
references.citation: J Biol Chem. 1998 Dec 4;273(49):32730-8
references.pmid: 9830016
references.citation: Peptides. 2002 Jul;23(7):1343-50
references.pmid: 12128091
references.citation: Arch Neurol. 1996 Aug;53(8):742-9
references.pmid: 8759980
references.citation: J Biol Chem. 2001 Jul 6;276(27):24540-8
references.pmid: 11337485
references.citation: Biochemistry. 1985 Apr 9;24(8):1909-14
references.pmid: 2410021
references.citation: Science. 1996 Oct 4;274(5284):99-102
references.pmid: 8810256
references.citation: J Neurochem. 2007 Jan;100(2):458-67
references.pmid: 17241160
references.citation: Bioessays. 1996 Jan;18(1):13-8
references.pmid: 8593159
references.citation: EMBO Rep. 2000 Dec;1(6):530-5
references.pmid: 11263499
references.citation: Peptides. 2002 Jul;23(7):1285-97
references.pmid: 12128085
references.citation: Neurosci Res. 2004 Jan;48(1):93-100
references.pmid: 14687885
references.citation: Neuron. 1994 Jul;13(1):45-53
references.pmid: 8043280
references.citation: J Biol Chem. 2006 Aug 25;281(34):24566-74
references.pmid: 16787929
references.citation: Nature. 2004 Aug 5;430(7000):631-9
references.pmid: 15295589
references.citation: Brain Res Bull. 2003 Aug 15;61(3):321-6
references.pmid: 12909302
references.citation: Nat Med. 2000 Feb;6(2):143-50
references.pmid: 10655101