Dietary resveratrol prevents Alzheimer's markers and increases life span in SAMP8

Abstract

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Figures

Fig. 1

Kaplan–Meier plot with data expressed as percentage of individuals alive (a, b) and median life span of the four groups studied (c). Mantel–Cox log-rank test analysis reveals a shift to the right for the resveratrol group in SAMP8 (a, P < 0.0001) and SAMR1 (b, P = 0.0051). In the median life span comparison (c) and maximum life span comparison considered as the mean of the final 20 % of mice surviving in each group (d), results are expressed as mean±SEM; ***P < 0.001 vs. SAMP8, ##P < 0.01 vs. SAMR1, ###P < 0.001 vs. SAMR1

Fig. 2

Discrimination index of both groups of SAMP8 animals. Only Rsv group values are positive and different from zero (*P < 0.05). There is a higher DI of Rsv animals than of SAMP8 control mice (#P < 0.05 vs. SAMP8 mice). Bars represent mean±SEM

Fig. 3

Levels of sirtuin 1 (a, b), its acetylated substrate p53 (c, d), p-AMPK (e, f), and AMPK (g, h). Bars represent mean±SEM and values are adjusted to 100 % for levels of SAMP8 control mice. Student’s paired t test; *P < 0.05; **P < 0.01 vs. SAMP8. Cortex (Cx), hippocampus (Hp)

Fig. 4

Representative hippocampal images of SAMP8 and SAMP8 Rsv animals (a), arrowheads (Aβ40 and Aβ42) indicate some clusters of amyloid granules in both groups. Quantification of the amount of Aβ42 (b) and Aβ40 (c) clusters in the hippocampus of the two groups. Bars represent mean±SEM; values in d–g are adjusted to 100 % for levels of SAMP8 control mice. Student’s paired t test; *P < 0.05 vs. SAMP8. Cortex (Cx), hippocampus (Hp)

Fig. 5

Cortex and hippocampal levels of BACE (a, b) and ADAM-10 (c, d) of SAMP8 and SAMP8 Rsv animals. Bars represent mean±SEM; values in a–d are adjusted to 100 % for levels of SAMP8 control mice. Student’s paired t test; *P < 0.05; **P < 0.01 vs. SAMP8. Cortex (Cx), hippocampus (Hp)

Fig. 6

Levels of phosphorylated tau (pTau) at Ser396 in the cortex (a) and hippocampus (b) of SAMP8 and SAMP8 Rsv groups. Cortex and hippocampal levels of CDK5 (c, d), P25/P35 ratio (e, f). Bars represent mean±SEM and values are adjusted to 100 % for levels of SAMP8 control mice. Student’s paired t test; *P < 0.05; **P < 0.01 vs. SAMP8. Cortex (Cx), hippocampus (Hp)

Fig. 7

Cortex and hippocampal levels of p-GSK3ß (phosphorylated in Ser9) (a, b). p-cdc2 (phosphorylated in Tyr15) (c, d) and JNK (phosphorylated in Thr183/Tyr185) (e, f). Bars represent mean±SEM and values are adjusted to 100 % for levels of SAMP8 control mice. Student’s paired t test: *P < 0.05 vs. SAMP8. Cortex (Cx), hippocampus (Hp)