Abstract
Autophagy, a crucial pathway for the degradation of proteins in eukaryotic cells, is linked to the development of Alzheimer’s disease (AD), and the accumulated autophagosomes in the cells resulting in the death of cells. Sevoflurane can impair spatial learning and memory in mice with AD and lead to the apoptosis of nerve cells; however, the underlying mechanisms remain unknown. We aim to explore the effects and underlying mechanisms of sevoflurane in APPswe/PS1ΔE9 double-transgenic mice. 51 heterozygous APPswe/PS1ΔE9 double-transgenic mice were involved and divided into three groups, including control group, sham group and sevoflurane group. Morris water maze experiment was used to test the learning and memory abilities of mice, flow cytometry was conducted to detect apoptosis and mitochondrial membrane potential of brain cells in mice, transmission electron microscopy was used to observe the number of autophagosomes at the axon in mice, and western blot was carried out to detect the expression of Bax, Bcl-2, LC3II, P62, KIF3B and DIC proteins of brain cells in mice. In our study, we found that significantly longer escape latencies, fewer crossings of the platform and shorter time spent in the target quadrant of the morris water maze experiment in the sevoflurane group. Flow cytometry showed cellular apoptosis was increased and the membrane potential of the mitochondria was reduced of brain cells in the sevoflurane group. Transmission electron microscopy displayed that there was a remarkable upregulation of autophagosomes at the axon of brain cells in mice after treatment of sevoflurane. Western blot demonstrated that the expression of Bax, LC3II, P62 and KIF3B proteins were elevated, and the expression of Bcl-2 and DIC proteins were reduced in the sevoflurane group. Sevoflurane impaired acquisition learning and memory function, promoted the apoptosis of hippocampal neurons in APPswe/PS1ΔE9 double-transgenic mice, and the mechanism might be related to the activation of autophagy along with the disruption of autophagosomes retrograde transport in axons.
Highlights
As of 2015, approximately 900 million individuals in the world are aged over 60 years, and the percentage of Alzheimer’s disease (AD) patients is about 5–7% [1]
Several studies have revealed that sevoflurane, the most widely used inhalable anesthetic, can impair spatial learning and memory in AD transgenic mice [4, 5], some studies report a different conclusion suggesting that general anesthesia may not be associated with the development of AD [6]
Significantly longer escape latencies were observed in the sevoflurane group (n = 8), and the escape latencies were shorter in the control group (n = 8) and sham group (n = 8) (Fig. 1a)
Summary
As of 2015, approximately 900 million individuals in the world are aged over 60 years, and the percentage of Alzheimer’s disease (AD) patients is about 5–7% [1]. With an increase in the elderly population worldwide, more AD patients require surgical treatment and general anesthesia. With the advantages of strong controllability, rapid onset, and fewer side effects, inhalable anesthetics including isoflurane, sevoflurane, and desflurane are widely used for general anesthesia. Several studies have revealed that sevoflurane, the most widely used inhalable anesthetic, can impair spatial learning and memory in AD transgenic mice [4, 5], some studies report a different conclusion suggesting that general anesthesia may not be associated with the development of AD [6]. More evidence is needed to explore the effect of inhalable anesthetics on AD
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