Depletion of vitamin E increases amyloid beta accumulation by decreasing its clearances from brain and blood in a mouse model of Alzheimer disease.
Increased oxidative damage is a prominent and early feature in Alzheimer disease. We previously crossed Alzheimer disease transgenic (APPsw) model mice with alpha-tocopherol transfer protein knock-out (Ttpa(-/-)) mice in which lipid peroxidation in the brain was significantly increased. The resulting double-mutant (Ttpa(-/-)APPsw) mice showed increased amyloid beta (Abeta) deposits in the brain, which was ameliorated with alpha-tocopherol supplementation. To investigate the mechanism of the increased Abeta accumulation, we here studied generation, degradation, aggregation, and efflux of Abeta in the mice. The clearance of intracerebral-microinjected (125)I-Abeta(1-40) from brain was decreased in Ttpa(-/-) mice to be compared with wild-type mice, whereas the generation of Abeta was not increased in Ttpa(-/-)APPsw mice. The activity of an Abeta-degrading enzyme, neprilysin, did not decrease, but the expression level of insulin-degrading enzyme was markedly decreased in Ttpa(-/-) mouse brain. In contrast, Abeta aggregation was accelerated in Ttpa(-/-) mouse brains compared with wild-type brains, and well known molecules involved in Abeta transport from brain to blood, low density lipoprotein receptor-related protein-1 (LRP-1) and p-glycoprotein, were up-regulated in the small vascular fraction of Ttpa(-/-) mouse brains. Moreover, the disappearance of intravenously administered (125)I-Abeta(1-40) was decreased in Ttpa(-/-) mice with reduced translocation of LRP-1 in the hepatocytes. These results suggest that lipid peroxidation due to depletion of alpha-tocopherol impairs Abeta clearances from the brain and from the blood, possibly causing increased Abeta accumulation in Ttpa(-/-)APPsw mouse brain and plasma.
Nishida
Yoichiro
Y
Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519. Japan.
Ito
Shingo
S
Ohtsuki
Sumio
S
Yamamoto
Naoki
N
Takahashi
Tsubura
T
Iwata
Nobuhisa
N
Jishage
Kou-Ichi
K
Yamada
Hiromi
H
Sasaguri
Hiroki
H
Yokota
Shigefumi
S
Piao
Wenying
W
Tomimitsu
Hiroyuki
H
Saido
Takaomi C
TC
Yanagisawa
Katsuhiko
K
Terasaki
Tetsuya
T
Mizusawa
Hidehiro
H
Yokota
Takanori
T
D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019587:Dietary Supplements; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D024505:Tocopherols / Q000378:metabolism*; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D002352:Carrier Proteins; C017763:alpha-tocopherol transfer protein; D053829:Amyloid Precursor Protein Secretases; D024502:alpha-Tocopherol; D024505:Tocopherols
Ann Neurol. 1999 Apr;45(4):537-41
10211483
Nat Med. 2004 Jul;10 Suppl:S18-25
15298006
Neurobiol Aging. 2004 Aug;25(7):833-41
15212837
Neurology. 1995 Aug;45(8):1594-601
7644059
Ann N Y Acad Sci. 2004 Dec;1031:1-12
15753129
Pharm Res. 2006 Jul;23(7):1407-16
16779710
J Cell Biol. 1994 Jul;126(1):235-46
8027181
Biochem Biophys Res Commun. 2006 Feb 3;340(1):263-7
16364250
J Alzheimers Dis. 2003 Feb;5(1):1-8
12590160
Biochem Biophys Res Commun. 1999 Apr 21;257(3):787-91
10208861
J Clin Invest. 2005 Nov;115(11):3285-90
16239972
Proc Natl Acad Sci U S A. 2003 May 13;100(10):6221-6
12732730
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4537-41
7538675
Nat Rev Drug Discov. 2004 Mar;3(3):205-14
15031734
Methods Enzymol. 1999;309:305-18
10507032
J Pharmacokinet Biopharm. 1978 Dec;6(6):547-58
731417
J Pharmacol Exp Ther. 2005 Jun;313(3):1370-8
15743932
J Clin Invest. 2000 Dec;106(12):1489-99
11120756
FEBS Lett. 1997 May 12;408(1):105-8
9180278
J Neurochem. 1996 Apr;66(4):1717-25
8627330
Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7
12634421
J Neurochem. 2004 May;89(4):807-11
15140180
J Neurochem. 1997 May;68(5):2092-7
9109537
J Pharmacol Exp Ther. 1996 Jun;277(3):1550-9
8667222
Int J Dev Neurosci. 2004 Nov;22(7):475-84
15465277
Biochem Biophys Res Commun. 2006 Nov 24;350(3):530-6
17026966
Science. 1996 Oct 4;274(5284):99-102
8810256
Neurobiol Aging. 1992 Jul-Aug;13(4):493-500
1508300
FASEB J. 1991 Mar 1;5(3):278-86
2001787
Pharmacol Ther. 2005 Nov;108(2):129-48
16112736
J Neurosci. 2004 Oct 27;24(43):9632-7
15509750
J Neurosci. 2002 Nov 1;22(21):9298-304
12417655
Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3632-7
14978286
J Neurosci. 2004 May 19;24(20):4894-902
15152051
Science. 1996 Jul 5;273(5271):59-63
8658196
J Biol Chem. 1990 Oct 15;265(29):18035-40
2211679
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15185-90
11752462
Mol Pharmacol. 2007 Oct;72(4):850-5
17609417
J Biol Chem. 2004 Oct 29;279(44):45897-908
15322125
Pharmacogenetics. 2002 Oct;12(7):535-41
12360104
Ann N Y Acad Sci. 2005 Jun;1043:545-52
16037277
Nat Med. 2007 Sep;13(9):1029-31
17694066
J Pharmacobiodyn. 1981 Nov;4(11):879-85
7328489
J Neurochem. 2005 Nov;95(4):1156-66
16271049