title: Blueberry opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activation protein kinase.
abstract: Alzheimer's Disease (AD) is the most common age-related dementia, with a current prevalence in excess of five million individuals in the United States. The aggregation of amyloid-beta (A beta) into fibrillar amyloid plaques is a key pathological event in the development of the disease. Microglial proinflammatory activation is widely known to cause neuronal and synaptic damage that correlates with cognitive impairment in AD. However, current pharmacological attempts at reducing neuroinflammation mediated via microglial activation have been largely negative in terms of slowing AD progression. Previously, we have shown that microglia express proinflammatory cytokines and a reduced capacity to phagocytose A beta in the context of CD40, A beta peptides and/or lipopolysaccharide (LPS) stimulation, a phenomenon that can be opposed by attenuation of p44/42 mitogen-activated protein kinase (MAPK) signaling. Other groups have found that blueberry (BB) extract both inhibits phosphorylation of this MAPK module and also improves cognitive deficits in AD model mice. Given these considerations and the lack of reduced A beta quantities in behaviorally improved BB-fed mice, we wished to determine whether BB supplementation would alter the microglial proinflammatory activation state in response to A beta. We found that BB significantly enhances microglial clearance of A beta, inhibits aggregation of A beta(1-42), and suppresses microglial activation, all via suppression of the p44/42 MAPK module. Thus, these data may explain the previously observed behavioral recovery in PSAPP mice and suggest a means by which dietary supplementation could mitigate an undesirable microglial response toward fibrillar A beta.
authors.affiliation: Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, Tampa, Florida 33613, USA.
authors.forename: Yuyan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Paula C
authors.initials: PC
authors.lastname: Bickford
authors.forename: Paul
authors.initials: P
authors.lastname: Sanberg
authors.forename: Brian
authors.initials: B
authors.lastname: Giunta
authors.forename: Jun
authors.initials: J
authors.lastname: Tan
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D029798:Blueberry Plants; D002478:Cells, Cultured; D004032:Diet; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D051379:Mice; D017628:Microglia / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D010587:Phagocytosis / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology
chemical_list: D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D010936:Plant Extracts; C075222:amyloid beta-protein (1-42); D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
references.citation: J Exp Med. 1995 Jul 1;182(1):147-54
references.pmid: 7790814
references.citation: Nature. 1996 Aug 22;382(6593):716-9
references.pmid: 8751442
references.citation: Neurochem Int. 2002 Nov;41(5):345-52
references.pmid: 12176077
references.citation: Neurology. 1999 Jul 13;53(1):197-201
references.pmid: 10408559
references.citation: Neurosci Lett. 2007 Apr 6;416(1):87-91
references.pmid: 17317005
references.citation: J Neuropathol Exp Neurol. 2007 Aug;66(8):683-6
references.pmid: 17882012
references.citation: Curr Med Chem. 2007;14(27):2865-71
references.pmid: 18045132
references.citation: J Neurosci Res. 2006 Aug 1;84(2):427-33
references.pmid: 16676329
references.citation: J Rheumatol Suppl. 2001 Jun;62:10-5
references.pmid: 11409152
references.citation: J Immunol. 1999 Dec 15;163(12):6614-21
references.pmid: 10586056
references.citation: Crit Care Nurs Q. 2008 Jan-Mar;31(1):65-72
references.pmid: 18316939
references.citation: Can J Neurol Sci. 1989 Nov;16(4 Suppl):516-27
references.pmid: 2804814
references.citation: J Neurosci. 2002 Jul 15;22(14):6114-20
references.pmid: 12122072
references.citation: J Neuroimmunol. 2002 Nov;132(1-2):49-59
references.pmid: 12417433
references.citation: Brain Res. 2001 Feb 9;891(1-2):42-53
references.pmid: 11164808
references.citation: Lancet. 2001 Aug 11;358(9280):455-60
references.pmid: 11513909
references.citation: J Biol Chem. 1999 Nov 5;274(45):32301-8
references.pmid: 10542270
references.citation: J Biol Chem. 1996 Jul 26;271(30):18032-44
references.pmid: 8663372
references.citation: Eur J Immunol. 2005 Mar;35(3):901-10
references.pmid: 15688347
references.citation: Neurology. 2000 Feb 8;54(3):588-93
references.pmid: 10680787
references.citation: Neurosci Lett. 1990 Oct 30;119(1):32-6
references.pmid: 2097581
references.citation: J Cell Biol. 1998 May 18;141(4):1019-30
references.pmid: 9585419
references.citation: Brain Res. 2006 Dec 6;1123(1):216-225
references.pmid: 17078933
references.citation: J Rheumatol. 2000 Dec;27(12):2927-31
references.pmid: 11128688
references.citation: Brain Res Bull. 2003 Aug 15;61(3):255-60
references.pmid: 12909295
references.citation: FASEB J. 2003 Jan;17(1):118-20
references.pmid: 12424218
references.citation: J Cell Biol. 2001 Oct 15;155(2):217-26
references.pmid: 11604419
references.citation: J Alzheimers Dis. 2006;9(3 Suppl):271-6
references.pmid: 16914866
references.citation: Drugs Aging. 2000 Jul;17(1):1-11
references.pmid: 10933512
references.citation: Ann N Y Acad Sci. 2000;917:154-64
references.pmid: 11268339
references.citation: J Neurosci Res. 2007 Apr;85(5):1010-7
references.pmid: 17265471
references.citation: J Neurosci Res. 1992 Dec;33(4):549-58
references.pmid: 1484388
references.citation: J Biol Chem. 2002 Aug 16;277(33):29889-96
references.pmid: 12032144
references.citation: Science. 1999 Dec 17;286(5448):2352-5
references.pmid: 10600748
references.citation: Neurology. 2002 Apr 9;58(7):1050-4
references.pmid: 11940691
references.citation: Nutr Neurosci. 2004 Apr;7(2):75-83
references.pmid: 15279493
references.citation: Protein Sci. 1993 Mar;2(3):404-10
references.pmid: 8453378
references.citation: Exp Neurol. 1990 Oct;110(1):93-104
references.pmid: 1698655
references.citation: J Neurosci. 2000 Oct 15;20(20):7587-94
references.pmid: 11027218
references.citation: Brain Res Brain Res Rev. 2005 Apr;48(2):234-9
references.pmid: 15850662
references.citation: Brain Res. 2000 Dec 1;885(1):117-21
references.pmid: 11121537
references.citation: Neurology. 1993 Aug;43(8):1609-11
references.pmid: 8351023
references.citation: Acta Neuropathol. 1989;77(6):569-75
references.pmid: 2750476
references.citation: Gerontology. 2008;54(1):6-17
references.pmid: 18160818
references.citation: J Neurosci. 1998 Jun 15;18(12):4451-60
references.pmid: 9614222
references.citation: Microsc Res Tech. 2001 Jul 15;54(2):59-70
references.pmid: 11455613
references.citation: Dement Geriatr Cogn Disord. 2007;23(1):8-21
references.pmid: 17068392
references.citation: Nature. 1996 Aug 22;382(6593):685-91
references.pmid: 8751438
references.citation: Exp Neurol. 2005 May;193(1):75-84
references.pmid: 15817266
references.citation: J Neurosci. 2003 Apr 1;23(7):2665-74
references.pmid: 12684452
references.citation: PLoS One. 2008 May 14;3(5):e2135
references.pmid: 18478117
references.citation: J Neuroimmunol. 1989 Oct;24(3):173-82
references.pmid: 2808689
references.citation: Neurobiol Aging. 1988 Jul-Aug;9(4):339-49
references.pmid: 3263583
references.citation: J Neurosci. 2008 Feb 27;28(9):2221-30
references.pmid: 18305255
references.citation: Neurology. 2000 Nov 14;55(9):1278-83
references.pmid: 11087768
references.citation: Neurobiol Aging. 1999 Jul-Aug;20(4):395-405
references.pmid: 10604432
references.citation: Brain Res. 1999 Jun 5;830(2):226-36
references.pmid: 10366679
references.citation: Hum Mutat. 2005 Jul;26(1):29-35
references.pmid: 15895461
references.citation: J Neurosci. 1999 Sep 15;19(18):8114-21
references.pmid: 10479711
references.citation: Nihon Ronen Igakkai Zasshi. 2000 Mar;37(3):212-5
references.pmid: 10879069
references.citation: Neuropharmacology. 1999 Jul;38(7):1017-25
references.pmid: 10428420
references.citation: Brain Pathol. 2008 Jan;18(1):86-95
references.pmid: 18042261
references.citation: Muscle Nerve. 2002 Oct;26(4):459-70
references.pmid: 12362410
references.citation: J Agric Food Chem. 2002 Apr 10;50(8):2432-8
references.pmid: 11929309
references.citation: Int J Clin Exp Pathol. 2008 Jan 01;1(3):260-75
references.pmid: 18784813
references.citation: J Biol Chem. 1999 Feb 26;274(9):5835-42
references.pmid: 10026206
references.citation: Nutr Neurosci. 2003 Jun;6(3):153-62
references.pmid: 12793519
references.citation: Ann Neurol. 2007 Nov;62(5):504-14
references.pmid: 17879969
references.citation: Neuromolecular Med. 2002;1(1):1-31
references.pmid: 12025813
references.citation: J Neuroinflammation. 2005 Jun 03;2:14
references.pmid: 15935098