Blueberry opposes beta-amyloid peptide-induced microglial activation via inhibition of p44/42 mitogen-activation protein kinase.
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.
Zhu
Yuyan
Y
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.
Bickford
Paula C
PC
Sanberg
Paul
P
Giunta
Brian
B
Tan
Jun
J
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
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
J Exp Med. 1995 Jul 1;182(1):147-54
7790814
Nature. 1996 Aug 22;382(6593):716-9
8751442
Neurochem Int. 2002 Nov;41(5):345-52
12176077
Neurology. 1999 Jul 13;53(1):197-201
10408559
Neurosci Lett. 2007 Apr 6;416(1):87-91
17317005
J Neuropathol Exp Neurol. 2007 Aug;66(8):683-6
17882012
Curr Med Chem. 2007;14(27):2865-71
18045132
J Neurosci Res. 2006 Aug 1;84(2):427-33
16676329
J Rheumatol Suppl. 2001 Jun;62:10-5
11409152
J Immunol. 1999 Dec 15;163(12):6614-21
10586056
Crit Care Nurs Q. 2008 Jan-Mar;31(1):65-72
18316939
Can J Neurol Sci. 1989 Nov;16(4 Suppl):516-27
2804814
J Neurosci. 2002 Jul 15;22(14):6114-20
12122072
J Neuroimmunol. 2002 Nov;132(1-2):49-59
12417433
Brain Res. 2001 Feb 9;891(1-2):42-53
11164808
Lancet. 2001 Aug 11;358(9280):455-60
11513909
J Biol Chem. 1999 Nov 5;274(45):32301-8
10542270
J Biol Chem. 1996 Jul 26;271(30):18032-44
8663372
Eur J Immunol. 2005 Mar;35(3):901-10
15688347
Neurology. 2000 Feb 8;54(3):588-93
10680787
Neurosci Lett. 1990 Oct 30;119(1):32-6
2097581
J Cell Biol. 1998 May 18;141(4):1019-30
9585419
Brain Res. 2006 Dec 6;1123(1):216-225
17078933
J Rheumatol. 2000 Dec;27(12):2927-31
11128688
Brain Res Bull. 2003 Aug 15;61(3):255-60
12909295
FASEB J. 2003 Jan;17(1):118-20
12424218
J Cell Biol. 2001 Oct 15;155(2):217-26
11604419
J Alzheimers Dis. 2006;9(3 Suppl):271-6
16914866
Drugs Aging. 2000 Jul;17(1):1-11
10933512
Ann N Y Acad Sci. 2000;917:154-64
11268339
J Neurosci Res. 2007 Apr;85(5):1010-7
17265471
J Neurosci Res. 1992 Dec;33(4):549-58
1484388
J Biol Chem. 2002 Aug 16;277(33):29889-96
12032144
Science. 1999 Dec 17;286(5448):2352-5
10600748
Neurology. 2002 Apr 9;58(7):1050-4
11940691
Nutr Neurosci. 2004 Apr;7(2):75-83
15279493
Protein Sci. 1993 Mar;2(3):404-10
8453378
Exp Neurol. 1990 Oct;110(1):93-104
1698655
J Neurosci. 2000 Oct 15;20(20):7587-94
11027218
Brain Res Brain Res Rev. 2005 Apr;48(2):234-9
15850662
Brain Res. 2000 Dec 1;885(1):117-21
11121537
Neurology. 1993 Aug;43(8):1609-11
8351023
Acta Neuropathol. 1989;77(6):569-75
2750476
Gerontology. 2008;54(1):6-17
18160818
J Neurosci. 1998 Jun 15;18(12):4451-60
9614222
Microsc Res Tech. 2001 Jul 15;54(2):59-70
11455613
Dement Geriatr Cogn Disord. 2007;23(1):8-21
17068392
Nature. 1996 Aug 22;382(6593):685-91
8751438
Exp Neurol. 2005 May;193(1):75-84
15817266
J Neurosci. 2003 Apr 1;23(7):2665-74
12684452
PLoS One. 2008 May 14;3(5):e2135
18478117
J Neuroimmunol. 1989 Oct;24(3):173-82
2808689
Neurobiol Aging. 1988 Jul-Aug;9(4):339-49
3263583
J Neurosci. 2008 Feb 27;28(9):2221-30
18305255
Neurology. 2000 Nov 14;55(9):1278-83
11087768
Neurobiol Aging. 1999 Jul-Aug;20(4):395-405
10604432
Brain Res. 1999 Jun 5;830(2):226-36
10366679
Hum Mutat. 2005 Jul;26(1):29-35
15895461
J Neurosci. 1999 Sep 15;19(18):8114-21
10479711
Nihon Ronen Igakkai Zasshi. 2000 Mar;37(3):212-5
10879069
Neuropharmacology. 1999 Jul;38(7):1017-25
10428420
Brain Pathol. 2008 Jan;18(1):86-95
18042261
Muscle Nerve. 2002 Oct;26(4):459-70
12362410
J Agric Food Chem. 2002 Apr 10;50(8):2432-8
11929309
Int J Clin Exp Pathol. 2008 Jan 01;1(3):260-75
18784813
J Biol Chem. 1999 Feb 26;274(9):5835-42
10026206
Nutr Neurosci. 2003 Jun;6(3):153-62
12793519
Ann Neurol. 2007 Nov;62(5):504-14
17879969
Neuromolecular Med. 2002;1(1):1-31
12025813
J Neuroinflammation. 2005 Jun 03;2:14
15935098