Oxidative stress impairs learning and memory in apoE knockout mice.
Cardiovascular risk factors, such as oxidative stress and elevated lipids, are linked to the development of cognitive impairment. A mediator common to both stressors is the apolipoprotein E (apoE). The objectives of this study are to determine the effects of apoE deficiency and diet-induced systemic oxidative stress in mice on vascular expression of inflammatory proteins and on cognitive function. Mice are placed on a diet enriched in homocysteine for fifteen weeks and then assessed for spatial learning using an eight-arm radial maze and for inflammatory protein expression by immunohistochemistry. Our results show that diet-induced oxidative stress does not affect cognitive function in normal mice. In contrast, apoE-/- mice on the homocysteine diet show significantly impaired (p<0. 001) maze performance. ApoE-/- mice also have high cholesterol levels. There is no expression of inflammatory proteins IL-6 and IL-8 in the vasculature of control mice on normal or homocysteine diet and little in apoE-/- mice on normal diet. In contrast, apoE-/- mice on homocysteine diet show pronounced vascular reactivity to IL-6 and IL-8 antibodies. These data show that systemic oxidative stress correlates with expression of inflammatory proteins in the cerebral vasculature and impaired cognitive function. These results are consistent with the hypothesis that an oxidative-inflammatory cycle in the cerebral vasculature could have deleterious consequences for cognition.
Evola
Marianne
M
Garrison Institute on Aging, Department of Neurology, Department of Pharmacology and Neurosciences Texas Tech University Health Sciences Center, and Department of Psychology Texas Tech University, Lubbock, TX 79430, United States.
Hall
Allyson
A
Wall
Trevor
T
Young
Alice
A
Grammas
Paula
P
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D003071:Cognition / Q000502:physiology; D004032:Diet; D006710:Homocysteine / Q000008:administration & dosage; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D001057:Apolipoproteins E; D015850:Interleukin-6; D016209:Interleukin-8; D006710:Homocysteine; D002784:Cholesterol
Acta Neuropathol. 2009 Jul;118(1):103-13
19319544
Curr Drug Metab. 2007 Jan;8(1):17-31
17266521
J Alzheimers Dis. 2006 Aug;9(4):381-92
16917146
Microsc Res Tech. 2000 Aug 15;50(4):287-90
10936882
Alzheimer Dis Assoc Disord. 2009 Jan-Mar;23(1):1-10
18703981
Arterioscler Thromb Vasc Biol. 2004 Jun;24(6):1006-14
15087308
J Neurosci. 2005 Sep 21;25(38):8680-5
16177036
Ann Neurol. 2002 Mar;51(3):285-9
11891822
Evid Based Ment Health. 2002 Nov;5(4):126
12440468
Neurology. 2002 Nov 12;59(9):1375-80
12427887
Neurobiol Aging. 2003 Jan-Feb;24(1):187-90
12493565
Biochem Biophys Res Commun. 1994 Nov 30;205(1):659-65
7528015
Am J Clin Nutr. 2000 Feb;71(2):643S-649S
10681273
J Clin Invest. 1985 Oct;76(4):1501-13
3932467
Isr Med Assoc J. 2002 Mar;4(3):187-90
11908260
Eur J Neurosci. 2000 Jul;12(7):2235-42
10947802
Int J Geriatr Psychiatry. 2002 Sep;17(9):859-64
12221661
Annu Rev Nutr. 1999;19:217-46
10448523
Annu Rev Genomics Hum Genet. 2000;1:507-37
11701639
Dement Geriatr Cogn Disord. 2009;27(1):11-7
19088473
Nutr Clin Care. 2002 May-Jun;5(3):124-32
12134567
Neuroscience. 2002;114(3):641-54
12220566
Neurobiol Dis. 2000 Aug;7(4):321-31
10964604
Am J Physiol Cell Physiol. 2007 Apr;292(4):C1256-62
16870825
Neurology. 2002 May 28;58(10):1471-5
12034781
Clin Lab. 2002;48(9-10):471-81
12389706
Neurology. 2002 Nov 12;59(9):1475; author reply 1475-6
12427917
Antioxid Redox Signal. 2007 Nov;9(11):1941-58
17822365
Proc Natl Acad Sci U S A. 1985 Jan;82(1):203-7
3918303
Behav Brain Res. 2007 Jan 25;176(2):372-5
17126420
Brain Res Cogn Brain Res. 1996 Jun;3(3-4):167-81
8806020
Am J Geriatr Psychiatry. 2008 May;16(5):343-54
18448847
Arch Neurol. 2000 Oct;57(10):1439-43
11030795
Bull Exp Biol Med. 2008 Jul;146(1):33-5
19145343
Neuromolecular Med. 2003;4(3):197-202
14716026
Mol Cell Biochem. 2009 Jun;326(1-2):121-9
19116777
J Alzheimers Dis. 2006 Mar;9(1):51-8
16627934
N Engl J Med. 2002 Jun 20;346(25):2007; author reply 2008
12078704
Ann N Y Acad Sci. 2002 Nov;977:232-8
12480755
Stroke. 2002 Oct;33(10):2351-6
12364720
Mem Cognit. 1993 Mar;21(2):146-55
8469122
Neurobiol Aging. 2001 Nov-Dec;22(6):837-42
11754990
Stroke. 2002 Oct;33(10):2343-4
12364715
Brain Res. 1998 Mar 30;788(1-2):151-9
9554991
Dement Geriatr Cogn Disord. 2002;14(1):7-12
12053126
Psychon Bull Rev. 2005 Oct;12(5):769-86
16523997
Behav Brain Res. 2005 Apr 15;159(1):1-14
15794991
Neurol Neurochir Pol. 2009 Jul-Aug;43(4):321-9
19742390
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13124-31
15331782
N Engl J Med. 2002 Jun 20;346(25):2007; author reply 2008
12075065
Curr Mol Med. 2009 Apr;9(3):315-23
19355913