Aβ and tau toxicities in Alzheimer's are linked via oxidative stress-induced p38 activation: protective role of vitamin E

Abstract

Oxidative stress is a hallmark of Alzheimer's disease (AD). We propose that rather than causing damage because of the action of free radicals, oxidative stress deranges signaling pathways leading to tau hyperphosphorylation, a hallmark of the disease. Indeed, incubation of neurons in culture with 5 µM beta-amyloid peptide (Aβ) causes an activation of p38 MAPK (p38) that leads to tau hyperphosphorylation. Inhibition of p38 prevents Aβ-induced tau phosphorylation. Aβ-induced effects are prevented when neurons are co-incubated with trolox (the water-soluble analog of vitamin E). We have confirmed these results in vivo, in APP/PS1 double transgenic mice of AD. We have found that APP/PS1 transgenic mice exhibit a high level of P-p38 in the hippocampus but not in cortex and this is prevented by feeding animals with a diet supplemented with vitamin E. Our results underpin the role of oxidative stress in the altered cell signaling in AD pathology and suggest that antioxidant prevention may be useful in AD therapeutics.

Keywords: Antioxidant; Beta-amyloid; P-p38; Vitamin E.

Fig. 1

Trolox prevents Aβ dependent p38 activation in neurons in primary culture. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. Data were normalized with tubulin values. ^**p < 0.01 compared to control values; ⁺⁺p< 0.01 compared to values obtained with Aβ.

Fig. 2

Vitamin E supplementation prevents activation of p38 in AD mice in vivo. Representative Western blots are shown. In all cases, values are means ± SD of 9 mice (A) or 6 mice (B). Data were normalized with tubulin values, ^*p < 0.05 compared to values found in wild type mice (WT) or in mice fed with standard diet (TG).

Fig. 3

P38 activation leads to an increase in p-tau. Cultured neurons were pre-incubated with a p38 inhibitor (SB203580) for 30 min. Prior to the treatment with 5 µM of Aβ. Results showed that when p38 is inhibited there is a decrease in tau-phosphorylation compared to neurons without p38 inhibitor. Representative Western blots are shown. In all cases, values are means ± SD of 4 experiments. ^**p < 0.01 compared to control values. ⁺p < 0.05 compared to values obtained with Aβ.

Fig. 4

Effect of Aβ peptide and trolox in the expression of p-tau. Cultured neurons treated with 5 µM of Aβ showed significantly higher expression of p-tau (p < 0.05). Trolox reverted the Aβ-induced effects. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. ^**p < 0.05 compared to control values. ⁺p < 0.05 compared to values obtained with Aβ.

Fig. 5

P-tau in AD mice model. P-tau was higher in the hippocampus of AD transgenic mice compared to wild type mice. Representative Western blots are shown. In all cases, values are means ± SD of 9 experiments. ^*p < 0.05 compared to WT animals.

Fig. 6

Schematic representation of the role of oxidative stress linking Aβ and tau toxicities. Numbers near the arrows indicate the pertinent reference in the reference list. Figures refer to those in the paper.