Brain inflammation and oxidative stress in a transgenic mouse model of Alzheimer-like brain amyloidosis

Abstract

BACKGROUND: An increasing body of evidence implicates both brain inflammation and oxidative stress in the pathogenesis of Alzheimer's disease (AD). The relevance of their interaction in vivo, however, is unknown. Previously, we have shown that separate pharmacological targeting of these two components results in amelioration of the amyloidogenic phenotype of a transgenic mouse model of AD-like brain amyloidosis (Tg2576). METHODS: In the present study, we investigated the therapeutic effects of a combination of an anti-inflammatory agent, indomethacin, and a natural anti-oxidant, vitamin E, in the Tg2576 mice. For this reason, animals were treated continuously from 8 (prior to Abeta deposition) through 15 (when Abeta deposits are abundant) months of age. RESULTS: At the end of the study, these therapeutic interventions suppressed brain inflammatory and oxidative stress responses in the mice. This effect was accompanied by significant reductions of soluble and insoluble Abeta1-40 and Abeta1-42 in neocortex and hippocampus, wherein the burden of Abeta deposits also was significantly decreased. CONCLUSIONS: The results of the present study support the concept that brain oxidative stress and inflammation coexist in this animal model of AD-like brain amyloidosis, but they represent two distinct therapeutic targets in the disease pathogenesis. We propose that a combination of anti-inflammatory and anti-oxidant drugs may be a useful strategy for treating AD.

Figure 1

Effect of indomethacin plus vitamin E supplementation on markers of brain oxidative stress. Total cerebral cortex homogenates from Tg2576 receiving placebo (open bars) or the combination therapy (closed bars) were assayed for levels of iPF_2α-VI (upper panel) and protein carbonyls (lower panel) (*p < 0.01, n = 10 per group).

Figure 2

Effect of indomethacin plus vitamin E supplementation on GFAP levels. GFAP and actin levels were detected by immunoblots in homogenates from total cortex of Tg2576 administered with placebo (open bars) or indomethacin plus vitamin E (closed bars) (*p < 0.02, n = 8 per group).

Figure 3

Effect of indomethacin plus vitamin E supplementation on soluble Aβ levels. Levels of high salt soluble Aβ1-40 and Aβ1-42 in total cortex and hippocampus of Tg2576 on placebo (open bars), or indomethacin plus vitamin E (closed bars) (*p < 0.01, n = 8 per group).

Figure 4

Effect of indomethacin plus vitamin E supplementation on insoluble Aβ levels. Levels of formic acid soluble Aβ1-40 and Aβ1-42 in total cortex and hippocampus homogenates from Tg2576 receiving placebo (open bars) or indomethacin plus vitamin E (closed bars) (*p < 0.001, n = 8 per group).

Figure 5

Effect of indomethacin plus vitamin E supplementation on amyloid deposition. Percentage area of somatosensory cortex (SSC), hippocampus (HIP) and parahippocampal cortex (PHC) occupied by Aβ immunoreactive deposits in Tg2576 receiving placebo (open bars), or indomethacin plus vitamin E (closed bars) for seven months (*p < 0.001; n = 8 per group).

Figure 6

Representative pictures of brain sections from mice on placebo or receiving indomethacin plus vitamin E.