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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online December 4, 2003 as doi:10.1096/fj.03-0961fje. |
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Center for Experimental Therapeutics, Department of Pharmacology,
* Center for Neurodegenerative Disease Research,
Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
2Correspondence: Center for Experimental Therapeutics, University of Pennsylvania, BRB 2/3, Room 812, 421, Curie Blvd., Philadelphia, PA 19104, USA. E-mail: domenico{at}spirit.gcrc.upenn.edu
SPECIFIC AIMS
Increased brain oxidative stress is an early event in Alzheimer’s disease (AD) and has been implicated in its pathogenesis. The aim of the present study was to evaluate the effects of an antioxidant therapy (vitamin E) on the AD-like amyloidosis phenotype of a transgenic mouse model (Tg2576) when given before or after amyloid plaques are deposited.
PRINICPAL FINDINGS
1. Dietary vitamin E reduces brain oxidative stress
Starting at 5 months of age, a group of Tg2576 mice was randomized to receive placebo or vitamin E (2 I.U./g diet) added to the regular diet. Considering a mouse eats 
4–5 g chow/day and that the diet contained 2 I.U. of vitamin E per gram, the estimated average vitamin intake for each mouse was 8 I.U./day. At the end of the study, body weight, total plasma cholesterol, and triglyceride levels were not different between the two groups (not shown). Compliance with vitamin E intake was evident from the rise in plasma levels (20±2.1 vs. 47±1.9 µM, P<0.01) in mice receiving the supplemented diet. Administration of vitamin E significantly reduced 8,12-iso-iPF2
-VI levels in cortex (-60%) and hippocampus (-50%) homogenates compared with mice on placebo. This reduction inversely correlated with a significant increase of vitamin E levels in the same brain regions (data not shown).
Another group of Tg2576 was randomized to receive the same diet supplemented with vitamin E or placebo starting at 14 months of age until the mice were 20 months old. At the end of the study, body weight, total plasma cholesterol, and triglyceride levels were not different between the two groups. Similar to the previous group, mice receiving the supplemented diet showed a significant reduction in brain lipid peroxidation (-50%), accompanied by an increase in vitamin E levels (data not shown).
2. Dietary vitamin E reduces amyloid ß peptide formation in young but not in old Tg2576 mice
Levels of Aß1-40 and Aß1-42 in the high-salt and formic acid soluble fractions of brain homogenates were measured by a sensitive Aß sandwich ELISA. As expected for their age, we found that 13-month-old Tg2576 on placebo had discrete amounts of both peptide forms in their cortex and hippocampus (Fig. 1
, Fig. 2
). However, the younger Tg mice that were supplemented with vitamin E showed a significant reduction in Aß1-40 levels in both high-salt and formic acid soluble fractions (Fig. 1A
, Fig. 2A
). Similar results were observed for Aß1-42 (not shown). In contrast, animals that started receiving the vitamin E-supplemented diet when they were 14 months old did not show a significant difference between placebo and active treatment at the end of the treatment for Aß1-40 (Fig. 1B
, Fig. 2B
) and Aß1-42 levels (not shown).
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3. Dietary vitamin E reduces amyloid burden in young but not in old Tg2576 mice
Analysis of the amount of Aß brain deposition (i.e., amyloid plaque burden) by using immunohistochemistry further confirmed these observations. In accordance with published data, we found that 13-month-old animals on placebo had discrete amounts of Aß deposited in all three regions considered (somatosensory, hippocampus, and peri-hippocampus cortex). However, Tg2576 that received a diet supplemented with vitamin E starting at 5 months of age showed a significant reduction in the immunopositive areas consistent with a reduction in the amyloid burden. In sharp contrast, Tg2576 that received the supplemented diet starting at 14 months of age showed no significant difference in quantitative analyses of the immunopositive areas compared with the placebo-treated mice.
CONCLUSON AND SIGNIFICANCE
In this study, we report that vitamin E suppresses brain lipid peroxidation and significantly reduces Aß levels and amyloid plaque deposition in the Tg2576 mice when administered early during the evolution of their disease phenotype. By contrast, if vitamin E supplementation begins later, when amyloid plaques are already deposited, despite a reduction in brain oxidative stress, no significant effect is observed on the amyloidotic phenotype of these animals.
Extensive evidence for oxidative stress has been reported in AD, and several studies have consistently shown the presence of lipid, protein, and DNA oxidation products in postmortem as well as in living patients with the disease. Based on this evidence, a clinical trial with high-dose vitamin E was carried out in a subject with established clinical diagnosis of AD. The treatment had only a modest effect in slowing the decline of daily activities, but not cognitive decline. A possible explanation for these results is the fact that the vitamin was given too late, when the neuropathology was already well established.
For years it has been difficult to fully evaluate the contribution of oxidative processes to the neuropathology of AD. The recent development of transgenic mouse models of AD has allowed more controlled testing of the oxidative stress and Aß hypotheses of the AD pathogenesis.
The choice of using vitamin E at two different time points was based on our previous observations showing that the increase in brain lipid peroxidation precedes amyloid plaque formation and deposition in the Tg2576 mice, suggesting that brain oxidative damage is an early event and might contribute to AD-like phenotype early in the life span of this animal model.
The present findings support this new concept and suggest that at this stage oxidative stress plays a functional role in the amyloid cascade since only its early suppression is coincidental with a reduction in Aß levels and deposition (Fig. 3
). Taken together, these observations imply that any therapeutic strategy aimed to target oxidative stress should be initiated at the earliest possible stage of the disease, ideally in subjects at high risk for developing AD.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-0961fje; 
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