Sirt3 gene knockout protects mice from Alzheimer's disease through activating autophagy

Abstract

To investigate the protective effect of Sirt3 gene knockout on Alzheimer's disease (AD) in mice. The animal model of AD was established by intraperitoneal injection of D-galactose and brain-localized injection of amyloid β-protein (Aβ)1-40 in wild type C57BL/6 mice and Sirt3 gene knockout mice. Morris water maze, Y maze and tail suspension test were used to assess the cognitive function and anxiety-like behaviors in mice. Aβ deposition in the hippocampus was detected by immunofluorescent staining. Western blotting analysis was conducted to detect the expression of related proteins in the brain. Mouse cortical primary neurons were cultured and AD cell model was established. MTT assay was used to detect cell viability after modeling. Behavioral results showed that cognitive deficits were found in wide type mice after induction of AD as its prolonged escape latency (P<0.05) and decreased crossing number of platform and target zone duration (all P<0.05); while the knockout of Sirt3 alleviated cognitive deficit induced by AD (all P<0.05). Aβ immunofluorescence staining showed that the deposition of Aβ in the hippocampal region and expression of cleaved caspase 3 in the brain in Sirt3 knockout mice was reduced compared with that of wild type mice (all P<0.05). The expression of LC3-Ⅱ and P62 increased after AD was induced in wild type mice, while the autophagy in Sirt3 knockout mice was activated as the increase expression of LC3-Ⅱ and decrease expression of P62 (all P<0.05). In the AD cell model, the results of MTT assay were consistent with the animal experiments, and the protective effect of Sirt3 knockdown was eliminated after the treatment of the autophagy inhibitor chloroquine (all P<0.05). The knockdown of Sirt3 shows a protective effect on AD induced by D-galactose and Aβ1-40 in mice, which may be related to its function of activating autophagy.