Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis.
Oxidative stress is a key feature in the Alzheimer's disease (AD) brain and manifests as lipid peroxidation (LPO). Isoprostanes (iPs) are specific and sensitive markers of in vivo LPO. To determine whether amyloid beta (Abeta) deposition in vivo is associated with increased LPO, we examined iP levels in a transgenic mouse model (Tg2576) of AD amyloidosis. Urine, plasma, and brain tissues were collected from Tg2576 and littermate wild-type (WT) animals at different time points starting at 4 months of age and continuing until 18 months of age. Levels of urinary 8,12-iso-iPF(2alpha)-VI were higher in Tg2576 than in WT animals as early as 8 months of age and remained this high for the rest of the study. A similar pattern was observed for plasma levels of 8,12-iso-iPF(2alpha)-VI. Homogenates from the cerebral cortex and hippocampus of Tg2576 mice had higher levels of 8,12-iso-iPF(2alpha)-VI than those from WT mice starting at 8 months of age. In contrast, a surge of Abeta 1-40 and 1-42 levels as well as Abeta deposits in Tg2576 mouse brains occurred later, at 12 months of age. A direct correlation was observed between brain 8,12-iso-iPF(2alpha)-VI and Abeta 1-40 and 1-42. Because LPO precedes amyloid plaque formation in Tg2576 mice, this suggests that brain oxidative damage contributes to AD pathogenesis before Abeta accumulation in the AD brain.
Praticò
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Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. domenico@spirit.gcrc.upenn.edu
Uryu
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K
Leight
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Trojanoswki
J Q
JQ
Lee
V M
VM
D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000686:Amyloidosis / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology
C115626:8,12-iso-isoprostane F2alpha-VI; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D015237:Dinoprost