title: Regulation of IL-1β-induced cyclooxygenase-2 expression by interactions of Aβ peptide, apolipoprotein E and nitric oxide in human neuroglioma.
abstract: Alzheimer disease (AD) is characterized by chronic neuroinflammation, which may lead to dysfunction in neuronal circuits. Although reactive microglia are found in association with accumulation of beta amyloid (Aβ) plaques in the AD brain, their contribution to neuronal cell loss remains speculative. A major genetic risk factor for sporadic AD is inheritance of the apolipoprotein (apo) E4 allele, which has been shown to contribute significantly to neurodegeneration in AD. Many studies have documented the ability of Aβ fibrils in vitro to induce microglia to undergo phenotypic activation, which results in the secretion and/or expression of a plethora of free radicals and pro-inflammatory mediators. These mediators, such as reactive nitrogen/oxygen species and IL-1β as well as cyclooxygenase-2 (COX-2) with associated prostaglandin E2 (PGE(2)), are believed to be neurotoxic and to contribute to the underlying cause of AD. We have used the human H4 neuroglioma cells as a model astroglial system to examine the interactions between IL-1β and nitric oxide (NO) as co-stimulators of Aβ(1-40) in enhancing the expression of COX-2 and production of PGE(2) in the presence of recombinant human apolipoprotein E4 (apoE4). Neither Aβ(1-40) nor its reverse sequence analog Aβ(40-1) alone had a significant effect on COX-2 expression and PGE(2) production in the cells. In contrast, after co-incubation with apoE4, Aβ(1-40) increased IL-1β-induced COX-2 expression and PGE(2) production. Aβ(12-28), which binds with high affinity to apoE4, blocked apoE4-mediated effects on Aβ(1-40). Furthermore, (±)-S-Nitroso-N-acetylpenicillamine (SNAP), an agent that releases nitric oxide (NO) in situ, alone did not affect IL-1β-induced COX-2 expression, but increased PGE(2) production only. Addition of Aβ(1-40) preincubated with apoE4 to H4 cells in the presence of SNAP led to an additive IL-1β-induced COX-2 expression and PGE(2) production. These observations indicate that increased PGE(2) resulted from increased nitrosative stress, which is enhanced by apoE4. Thus a molecular understanding of the interactions of apoE4 with Aβ, NO and IL-1β on the regulation of the COX-2/prostaglandin pathway may open new avenues in understanding the mechanism of development of neurodegenerative disease such as AD.
authors.affiliation: Astellas Pharma US Inc., Deerfield, IL 60015, USA.
authors.forename: Anju S
authors.initials: AS
authors.lastname: Samy
authors.forename: Orisa J
authors.initials: OJ
authors.lastname: Igwe
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D053327:Apolipoprotein E4 / Q000378:metabolism* / Q000502:physiology; D001932:Brain Neoplasms; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D005910:Glioma; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism* / Q000502:physiology; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D053583:Interleukin-1beta; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D009569:Nitric Oxide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
references.citation: Biochem Biophys Res Commun. 2001 Jan 19;280(2):558-60
references.pmid: 11162555
references.citation: J Neurochem. 2001 Feb;76(4):1050-6
references.pmid: 11181824
references.citation: J Submicrosc Cytol Pathol. 1999 Jul;31(3):313-23
references.pmid: 10626000
references.citation: Trends Pharmacol Sci. 1991 Nov;12(11):430-6
references.pmid: 1796497
references.citation: Am J Pathol. 1994 Nov;145(5):1030-5
references.pmid: 7977635
references.citation: Neuroscience. 2000;97(2):207-10
references.pmid: 10799751
references.citation: Curr Pharm Des. 2008;14(14):1443-51
references.pmid: 18537667
references.citation: Neurology. 1998 Apr;50(4):986-90
references.pmid: 9566383
references.citation: Proc Soc Exp Biol Med. 2000 Dec;225(3):200-6
references.pmid: 11082214
references.citation: J Neurosci. 1997 Apr 15;17(8):2653-7
references.pmid: 9092586
references.citation: Cell Mol Neurobiol. 2003 Oct;23(4-5):681-9
references.pmid: 14514024
references.citation: J Biol Chem. 2002 Jun 14;277(24):21821-8
references.pmid: 11912196
references.citation: J Neurochem. 1996 May;66(5):1963-70
references.pmid: 8780024
references.citation: Methods Find Exp Clin Pharmacol. 1994 Mar;16(2):141-51
references.pmid: 8007743
references.citation: Curr Opin Lipidol. 1999 Jun;10(3):207-17
references.pmid: 10431657
references.citation: Arch Neurol. 2001 Mar;58(3):487-92
references.pmid: 11255454
references.citation: Nature. 2000 Mar 23;404(6776):352-4
references.pmid: 10746713
references.citation: J Biol Chem. 1994 Sep 23;269(38):23403-6
references.pmid: 8089103
references.citation: Nat Rev Neurosci. 2004 May;5(5):347-60
references.pmid: 15100718
references.citation: Br J Pharmacol. 1997 Aug;121(7):1482-8
references.pmid: 9257931
references.citation: J Biol Chem. 1996 May 17;271(20):11689-93
references.pmid: 8662662
references.citation: Trends Neurosci. 1993 Aug;16(8):323-8
references.pmid: 7691008
references.citation: J Biol Chem. 2003 Mar 28;278(13):11612-22
references.pmid: 12499373
references.citation: Neurobiol Aging. 1996 Sep-Oct;17(5):773-80
references.pmid: 8892351
references.citation: Am J Pathol. 2008 Sep;173(3):762-72
references.pmid: 18669616
references.citation: Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):8098-102
references.pmid: 8367470
references.citation: Neurology. 1999 Oct 22;53(7):1495-8
references.pmid: 10534257
references.citation: J Biol Chem. 1996 May 3;271(18):10602-6
references.pmid: 8631862
references.citation: Biochemistry. 2001 Sep 25;40(38):11533-42
references.pmid: 11560502
references.citation: Ann N Y Acad Sci. 1994 Nov 17;738:69-75
references.pmid: 7832457
references.citation: J Leukoc Biol. 1999 Jun;65(6):792-9
references.pmid: 10380901
references.citation: J Alzheimers Dis. 2011;24(2):269-85
references.pmid: 21239853
references.citation: Neurobiol Aging. 1996 Sep-Oct;17(5):789-94
references.pmid: 8892353
references.citation: Nat Med. 2003 Jul;9(7):907-13
references.pmid: 12808450
references.citation: J Cereb Blood Flow Metab. 2000 Dec;20(12):1659-68
references.pmid: 11129782
references.citation: Nat Med. 2001 Apr;7(4):414-5
references.pmid: 11283664
references.citation: J Biol Chem. 1995 Apr 21;270(16):9039-42
references.pmid: 7721816
references.citation: Glia. 1995 Oct;15(2):167-72
references.pmid: 8567068
references.citation: Brain Res Mol Brain Res. 2005 Jun 13;137(1-2):202-12
references.pmid: 15950779
references.citation: J Neurosci. 2005 Mar 9;25(10):2566-75
references.pmid: 15758166
references.citation: Biochem Biophys Res Commun. 1988 Dec 30;157(3):1212-7
references.pmid: 3207421
references.citation: FEBS Lett. 1997 Jun 30;410(2-3):470-6
references.pmid: 9237685
references.citation: J Clin Invest. 2008 Dec;118(12):4002-13
references.pmid: 19033669
references.citation: Neuropathol Appl Neurobiol. 2003 Jun;29(3):231-8
references.pmid: 12787320
references.citation: Neurobiol Aging. 2002 Sep-Oct;23(5):655-64
references.pmid: 12392766
references.citation: J Alzheimers Dis. 2002 Jun;4(3):193-201
references.pmid: 12226538
references.citation: FASEB J. 2006 Mar;20(3):494-6
references.pmid: 16423877
references.citation: Rev Neurosci. 2006;17(5):497-523
references.pmid: 17180876
references.citation: Am J Pathol. 2004 Sep;165(3):937-48
references.pmid: 15331417
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2892-7
references.pmid: 10694577
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1977-81
references.pmid: 8446617
references.citation: Hum Pathol. 1995 Aug;26(8):816-23
references.pmid: 7635444
references.citation: Neuroscience. 2001;105(4):971-85
references.pmid: 11530235
references.citation: Brain Res. 1998 Mar 2;785(2):195-206
references.pmid: 9518610
references.citation: Subcell Biochem. 2005;38:255-72
references.pmid: 15709483
references.citation: Biochim Biophys Acta. 1996 Jan 17;1315(1):40-6
references.pmid: 8611645
references.citation: Ann Neurol. 2004 May;55(5):668-75
references.pmid: 15122707
references.citation: Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5644-51
references.pmid: 16567625
references.citation: Acta Neuropathol. 2000 Nov;100(5):451-8
references.pmid: 11045665
references.citation: J Mol Neurosci. 2004;23(3):189-204
references.pmid: 15181247
references.citation: FEBS Lett. 1997 Aug 18;413(2):314-8
references.pmid: 9280304
references.citation: J Alzheimers Dis. 2001 Feb;3(1):23-30
references.pmid: 12214069
references.citation: Ann Neurol. 2009 Jun;65(6):623-5
references.pmid: 19557874
references.citation: J Immunol. 2001 Oct 1;167(7):3962-71
references.pmid: 11564815
references.citation: Brain. 2008 Mar;131(Pt 3):651-64
references.pmid: 18292081
references.citation: Chem Res Toxicol. 1992 Nov-Dec;5(6):834-42
references.pmid: 1336991