Abstract:

Objective To discuss the effect of sesamin （Ses） regulating adenosine monophosphate （AMP）-activated protein kinase （AMPK）/silent information regulator 1 （SIRT1） autophagy pathway on the learning and memory abilities of rats with Alzheimer’s disease （AD）. Methods Ninety male SD rats were randomly divided into control group， model group， low dose of Ses group （Ses-L group）， high dose of Ses group （Ses-H group）， positive control Donepezil group（Donepezil group）， and high dose of Ses+AMPK inhibitor Compound C group （Ses-H+Compound C group）， with 15 rats in each group. Step-down test was used to examine the step-down latencies and numbers of electric shocks of the rats in various groups； Morris water maze test was used to detect the escape latency and number of platform crossings of the rats in various groups； HE staining was used to observe the pathological morphology of neurons in the hippocampal CA1 region of the rats in various groups； TUNEL staining was used to detect the apoptotic rate of neurons in the hippocampus tissue of the rats in various groups； transmission electron microscope was used to observe the formation of autophagosomes in the hippocampal CA1 region of the rats in various groups； Western blotting method was used to detect the expression levels of rabbit primary antibodies against Beclin1， microtubule-associated protein 1 light chain 3 （LC3）， AMPK， phosphorylated AMPK （p-AMPK）， and SIRT1 proteins in the hippocampus CA1 region tissue of the rats in various groups. Results The step-down test， Morris water maze test and HE staining results showed that compared with control group， the step-down latency of the rats in model group was shortened （P<0.05）， and the number of electric shocks was increased （P<0.05）； the escape latency was prolonged （P<0.05）， and the number of platform crossings was decreased （P<0.05）； most neurons showed pyknosis， the number of normal cells was reduced， and the apoptotic rate of neurons was increased （P<0.05）. Compared with model group， the step-down latencies of the rats in Ses-L group， Ses-H group and Donepezil group were prolonged （P<0.05）， and the numbers of electric shocks were decreased （P<0.05）； the escape latencies were shortened （P<0.05）， and the numbers of platform crossings were increased （P<0.05）； the structure and morphology of neurons in hippocampal CA1 region were improved， and the apoptotic rates of neurons were decreased （P<0.05）. Compared with Ses-L group， the step-down latencies of the rats in Ses-H group and Donepezil group were prolonged （P<0.05）， and the number of electric shocks were decreased （P<0.05）； the escape latency was shortened （P<0.05）， and the numbers of platform crossings were increased （P<0.05）； the pathological damage in hippocampal CA1 region was further alleviated， and the apoptotic rate of neurons were decreased （P<0.05）. Compared with Ses-H group， the step-down latency of the rats in Ses-H+Compound C group was shortened （P<0.05）， and the number of electric shocks was increased （P<0.05）； the escape latency was prolonged （P<0.05）， and the number of platform crossings was decreased （P<0.05）； a large number of pyknotic neurons were observed in hippocampal CA1 region， and the apoptotic rate of neurons was increased （P<0.05）. The TUNEL staining and Western blotting results showed that compared with control group， the number of autophagosomes in hippocampal CA1 region of the rats in model group was decreased， the expression levels of Beclin1 and SIRT1 proteins and the ratios of LC3-Ⅱ/LC3-Ⅰ and p-AMPK/AMPK were decreased （P<0.05）； compared with model group， the numbers of autophagosomes in hippocampal CA1 region of the rats in Ses-L group， Ses-H group and Donepezil group were increased， the expression levels of Beclin1 and SIRT1 proteins and the ratios of LC3-Ⅱ/LC3-Ⅰ and p-AMPK/AMPK were increased （P<0.05）； compared with Ses-L group， the numbers of autophagosomes in hippocampal CA1 region of the rats in Ses-H group and Donepezil group were increased， the expression levels of Beclin1 and SIRT1 proteins and the ratios of LC3-Ⅱ/LC3-Ⅰ and p-AMPK/AMPK were increased （P<0.05）； compared with Ses-H group， the number of autophagosomes in hippocampal CA1 region of the rats in Ses-H+Compound C group was decreased， the expression levels of Beclin1 and SIRT1 proteins and the ratios of LC3-Ⅱ/LC3-Ⅰ and p-AMPK/AMPK were decreased （P<0.05）. Conclusion Ses can improve the learning and memory abilities of AD model rats， which may be related to the activation of AMPK/SIRT1 autophagy pathway by Ses.

Key words: Sesamin, Activated protein kinase/Silent information regulator 1 autophagy pathway, Alzheimer’s disease, Learning and memory ability, Autophagy