title: The 5-lipoxygenase pathway: oxidative and inflammatory contributions to the Alzheimer's disease phenotype.
abstract: Alzheimer's disease (AD) is the most common, and, arguably, one of the most-well studied, neurodegenerative conditions. Several decades of investigation have revealed that amyloid-β and tau proteins are critical pathological players in this condition. Genetic analyses have revealed specific mutations in the cellular machinery that produces amyloid-β, but these mutations are found in only a small fraction of patients with the early-onset variant of AD. In addition to development of amyloid-β and tau pathology, oxidative damage and inflammation are consistently found in the brains of these patients. The 5-lipoxygenase protein enzyme (5LO) and its downstream leukotriene metabolites have long been known to be important modulators of oxidation and inflammation in other disease states. Recent in vivo evidence using murine knock-out models has implicated the 5LO pathway, which also requires the 5LO activating protein (FLAP), in the molecular pathology of AD, including the metabolism of amyloid-β and tau. In this manuscript, we will provide an overview of 5LO and FLAP, discussing their involvement in biochemical pathways relevant to AD pathogenesis. We will also discuss how the 5LO pathway contributes to the molecular and behavioral insults seen in AD and provide an assessment of how targeting these proteins could lead to therapeutics relevant not only for AD, but also other related neurodegenerative conditions.
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine Philadelphia, PA, USA.
authors: Yash B
authors: YB
authors: Joshi
authors: Department of Pharmacology and Center for Translational Medicine, Temple University School of Medicine Philadelphia, PA, USA.
authors: Domenico
authors: D
authors: Praticò
keywords: 5-lipoxygenase; Alzheimer’s disease; amyloid beta; memory; neuroinflammation; oxidative stress; synapse; tau
references: J Neuroinflammation. 2013 Jul 16;10:84
references: 23866266
references: Redox Rep. 2013;18(4):134-41
references: 23849337
references: J Neuropathol Exp Neurol. 2007 Dec;66(12):1136-46
references: 18090922
references: Neurosci Lett. 1992 Nov 23;147(1):58-62
references: 1336152
references: Neurochem Int. 2013 Feb;62(3):340-7
references: 23318673
references: J Neuroinflammation. 2012 Jun 14;9:127
references: 22697885
references: J Neurosci. 2013 Jun 19;33(25):10512-25
references: 23785163
references: Neurodegener Dis. 2014;13(1):17-23
references: 24021653
references: Biochem Soc Trans. 2011 Aug;39(4):886-90
references: 21787318
references: Curr Top Med Chem. 2011;11(12):1555-70
references: 21510832
references: FASEB J. 2008 Apr;22(4):1169-78
references: 17998412
references: N Engl J Med. 2005 Jun 9;352(23):2379-88
references: 15829527
references: J Neuroinflammation. 2012 Mar 07;9:47
references: 22397366
references: N Engl J Med. 1997 Apr 24;336(17):1216-22
references: 9110909
references: Cell Signal. 2012 May;24(5):981-90
references: 22286106
references: PLoS One. 2013;8(4):e59586
references: 23560052
references: J Neuropathol Exp Neurol. 1997 Mar;56(3):285-90
references: 9056542
references: Acta Neuropathol. 1997 Jul;94(1):1-5
references: 9224523
references: Curr Top Med Chem. 2013;13(15):1853-63
references: 23931438
references: Neurology. 1992 Feb;42(2):447-9
references: 1736183
references: Neurobiol Aging. 2013 Jun;34(6):1549-54
references: 23332172
references: Mech Ageing Dev. 2013 Mar;134(3-4):139-57
references: 23428415
references: J Neurochem. 1996 Jan;66(1):147-52
references: 8522947
references: N Engl J Med. 2013 Jul 25;369(4):341-50
references: 23883379
references: Neurology. 1997 Mar;48(3):626-32
references: 9065537
references: J Alzheimers Dis. 2014;41(2):615-31
references: 24662102
references: PLoS One. 2013;8(4):e60921
references: 23577177
references: JAMA. 2014 Jan 1;311(1):33-44
references: 24381967
references: Neurobiol Aging. 2004 May-Jun;25(5):675-83
references: 15172747
references: Neurobiol Dis. 2000 Dec;7(6 Pt B):682-9
references: 11114266
references: Brain Res. 1994 Aug 15;654(1):171-6
references: 7982093
references: J Neurochem. 2011 Apr;117(1):19-28
references: 21244429
references: Nature. 2012 Aug 2;488(7409):96-9
references: 22801501
references: Sci Transl Med. 2011 Apr 6;3(77):77sr1
references: 21471435
references: Biol Psychiatry. 2013 Sep 1;74(5):321-8
references: 23352590
references: Acta Neuropathol. 2013 Oct;126(4):479-97
references: 24052108
references: Biol Psychiatry. 2013 Sep 1;74(5):348-56
references: 23683389
references: J Neuropathol Exp Neurol. 1999 Sep;58(9):1010-9
references: 10499443
references: FEBS Lett. 2007 Apr 3;581(7):1269-74
references: 17349630
references: Exp Neurol. 2014 Jun;256:7-16
references: 24681156
references: Pharmacol Rep. 2012;64(5):1179-88
references: 23238474
references: Cardiovasc Psychiatry Neurol. 2009;2009:174657
references: 19936103
references: Allergy Asthma Immunol Res. 2014 Jul;6(4):288-95
references: 24991451
references: Folia Neuropathol. 2010;48(4):283-92
references: 21225511
references: Mol Neurodegener. 2012 Jan 05;7(1):1
references: 22222029
references: Curr Alzheimer Res. 2011 Aug;8(5):452-69
references: 21605052
references: Antioxid Redox Signal. 2013 Sep 10;19(8):823-35
references: 23249141
references: Alzheimers Dement. 2014 Mar;10(2):e47-92
references: 24818261
references: Neurosci Lett. 2000 May 19;285(3):165-8
references: 10806312
references: Biochim Biophys Acta. 2007 Aug;1768(8):1976-90
references: 17433250
references: Am J Pathol. 2011 Apr;178(4):1762-9
references: 21435457
references: J Neurosci. 2008 Aug 13;28(33):8354-60
references: 18701698
references: Ann Neurol. 2012 Sep;72(3):442-54
references: 23034916
references: N Engl J Med. 2013 Jan 10;368(2):107-16
references: 23150908
references: Neurology. 1996 Aug;47(2):425-32
references: 8757015
references: J Neuropsychiatry Clin Neurosci. 2001 Spring;13(2):304-5
references: 11449041
references: Neurobiol Aging. 2007 Sep;28(9):1457-62
references: 16930777
references: Curr Alzheimer Res. 2010 Dec;7(8):656-64
references: 20678074
references: Mol Psychiatry. 2014 Feb;19(2):159-67
references: 24393807
references: Evid Based Med. 2014 Aug;19(4):140
references: 24639394
references: Antioxid Redox Signal. 2010 Jan;12(1):125-69
references: 19624272
references: Acta Biochim Biophys Sin (Shanghai). 2013 Sep;45(9):709-19
references: 23752617
references: Neurobiol Aging. 2014 Nov;35(11):2458-2464
references: 24973121
references: J Histochem Cytochem. 2008 Dec;56(12):1065-73
references: 18678882
references: J Clin Invest. 1949 Sep;28(5 Pt 2):1163-71
references: 16695788
references: Neurobiol Aging. 2014 May;35(5):1024-31
references: 24332986
references: J Alzheimers Dis. 2013;37(4):849-56
references: 23948931
references: FEBS Lett. 1993 Dec 28;336(3):417-24
references: 8282104
references: Neurobiol Aging. 1999 May-Jun;20(3):325-30; discussion 339-42
references: 10588580
references: J Biol Chem. 2006 Jan 20;281(3):1599-604
references: 16282321
references: Biochem Biophys Res Commun. 2010 May 21;396(1):105-10
references: 20494120
references: Ann N Y Acad Sci. 2007 Feb;1097:114-45
references: 17413016
references: Yakugaku Zasshi. 2011;131(12):1843-53
references: 22129883
references: Endocrinology. 2011 Jul;152(7):2704-15
references: 21558319
references: Mol Psychiatry. 2014 Apr;19(4):511-8
references: 23478745
references: Ann Neurol. 2011 Jan;69(1):34-46
references: 21280074
references: Biochim Biophys Acta. 2012 May;1822(5):631-8
references: 22019723
references: FASEB J. 1998 Apr;12(6):439-49
references: 9535216