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The Journal of Neuroscience, June 15, 2001, 21(12):4183-4187
Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in
an Animal Model of Alzheimer Amyloidosis
Domenico
Praticò,
Kunihiro
Uryu,
Susan
Leight,
John Q.
Trojanoswki, and
Virginia M.-Y.
Lee
Center for Experimental Therapeutics and Department of
Pharmacology, Center for Neurodegenerative Disease Research, University
of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
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  (A) 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-iPF2 -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-iPF2-VI. Homogenates from
the cerebral cortex and hippocampus of Tg2576 mice had higher levels of
8,12-iso-iPF2-VI than those from WT mice
starting at 8 months of age. In contrast, a surge of A 1-40 and
1-42 levels as well as A deposits in Tg2576 mouse brains occurred
later, at 12 months of age. A direct correlation was observed between brain 8,12-iso-iPF2-VI and A 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 A accumulation in the AD brain.
Key words:
Alzheimer's disease; Tg2576 transgenic animal model; lipid peroxidation; isoprostanes; amyloid protein; plasma; urine
Copyright © 2001 Society for Neuroscience 0270-6474/01/21124183-05$05.00/0
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