Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease - PubMed (original) (raw)

Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer's disease

Sandra L Siedlak et al. Free Radic Res. 2009 Feb.

Abstract

Oxidative modifications are a hallmark of oxidative imbalance in the brains of individuals with Alzheimer's, Parkinson's and prion diseases and their respective animal models. While the causes of oxidative stress are relatively well-documented, the effects of chronically reducing oxidative stress on cognition, pathology and biochemistry require further clarification. To address this, young and aged control and amyloid-beta protein precursor-over-expressing mice were fed a diet with added R-alpha lipoic acid for 10 months to determine the effect of chronic antioxidant administration on the cognition and neuropathology and biochemistry of the brain. Both wild type and transgenic mice treated with R-alpha lipoic acid displayed significant reductions in markers of oxidative modifications. On the other hand, R-alpha lipoic acid had little effect on Y-maze performance throughout the study and did not decrease end-point amyloid-beta load. These results suggest that, despite the clear role of oxidative stress in mediating amyloid pathology and cognitive decline in ageing and AbetaPP-transgenic mice, long-term antioxidant therapy, at levels within tolerable nutritional guidelines and which reduce oxidative modifications, have limited benefit.

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Figures

Figure 1

Figure 1

Dot-blot analysis of total brain homogenate reveals striking differences in markers of oxidative damage. Specifically, in both wild-type and Tg2576 mice who received the LA-enriched diet, levels of HO-1 (A) and HNE (B) were reduced, in some cases significantly. Using this method, the amount of Aβ was also determined. In the Tg2576 mice, Aβ levels remained unchanged following the chronic LA diet (C).

Figure 2

Figure 2

Immunohistochemical analysis suggests accumulation of markers of oxidative damage in the brain is attenuated following chronic LA administration. HO-1, which accumulates around the Aβ depositions in the Tg2576 mice on normal diet (A), is reduced in the mice on the LA diet (C). Similarly, in the normal diet group, HNE accumulation surrounding the large Aβ plaques is evident (B), while essentially absent from all animals in the LA group (D). Scale bar = 50 µm.

Figure 3

Figure 3

Redox-active iron, detected using a histochemical technique on paraffin embedded tissue sections, specifically accumulates with Aβ in Tg2576 mice on normal diet (B) and is present at the same levels even in mice on the LA diet in Aβ plaques in the hippocampus and cortex (A).

Figure 4

Figure 4

Immunohistochemical analysis of Aβ density in the cortex and hippocampus, expressed as the percentage area covered by Aβ, as detected with antibody 4G8 in the Tg2576 mice. While the older mice have expectedly higher levels of Aβ deposition, those mice administered the LA-enriched diet for 10 months show no less Aβ deposition. Significantly, even in those mice beginning the diet at age 6–8 months, presumably before visible Aβ plaque development, by the end of the experiment after 10 months, Aβ deposition was also not attenuated.

Figure 5

Figure 5

Behaviour analysis, in this case administration of the Y-maze task, showed little change between the groups of mice on normal or LA-enriched diet. The number of arm entries, while higher in the Tg mice at the beginning of study in accordance with previous reports, decreased by the end of the study in all groups. No significant differences were noted between the mice on normal or LA-enriched diet (A). The percentage alternations, defined as entries into an arm different than the previous two choices, did not show any significant changes in any group (B).

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References

    1. Markesbery WR. Oxidative stress hypothesis in Alzheimer’s disease. Free Radic Biol Med. 1997;23:134–147. - PubMed
    1. Polidori MC, Griffiths HR, Mariani E, Mecocci P. Hallmarks of protein oxidative damage in neurodegenerative diseases: focus on Alzheimer’s disease. Amino Acids. 2007;32:553–559. - PubMed
    1. Perry G, Castellani RJ, Hirai K, Smith MA. Reactive oxygen species mediate cellular damage in Alzheimer disease. J Alzheimers Dis. 1998;1:45–55. - PubMed
    1. Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G. Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc Natl Acad Sci USA. 1994;91:5710–5714. - PMC - PubMed
    1. Castellani RJ, Harris PL, Sayre LM, Fujii J, Taniguchi N, Vitek MP, Founds H, Atwood CS, Perry G, Smith MA. Active glycation in neurofibrillary pathology of Alzheimer disease: N(epsilon)-(carboxymethyl) lysine and hexitol-lysine. Free Radic Biol Med. 2001;31:175–180. - PubMed

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