Dexmedetomidine mediates the mechanism of action of ferroptosis in mice with Alzheimer’s disease by regulating the mTOR-TFR1 pathway

Abstract

BACKGROUND

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and there are currently no effective drugs to delay progression of the disease. Ferroptosis may play a vital part in AD, and is therefore receiving increasing attention by researchers.

AIM

To investigate the effects of dexmedetomidine (Dex) on ferroptosis in AD mouse hippocampus.

METHODS

Hippocampal neurons (HNs) HT22 were induced by amyloid β-protein (Aβ) and both in vitro and in vivo AD mouse models were prepared via injections. The cell-counting kit-8 assay and immunofluorescence technique were adopted to determine cell proliferation activity and intracellular Fe²⁺ levels, and the TBA method and microplate method were employed for malondialdehyde and glutathione measurements, respectively. Hippocampal tissue damage was determined using hematoxylin and eosin and Nissl staining. Mouse learning and memory ability in each group was assessed by the Morris water maze test, and the expression levels of mammalian target of rapamycin (mTOR) signal molecules and ferroptosis-related proteins transferrin receptor 1 (TFR1), SLC7A11 and glutathione peroxidase 4 were examined by western blotting.

RESULTS

Dex enhanced lipid peroxidation and iron influx in mouse HNs in both in vitro and in vivo experiments, while inhibition of the mTOR axis blocked this process. These findings demonstrate that Dex can inhibit ferroptosis-induced damage in mouse HNs by activating mTOR-TFR1 signaling to regulate ferroptosis-associated proteins, thus alleviating cognitive dysfunction in AD mice.

CONCLUSION

Dex can activate the mTOR-TFR1 axis to inhibit ferroptosis in mouse HNs, thereby improving the learning and memory ability of mice.

Keywords: Dexmedetomidine; Ferroptosis; Alzheimer’s disease; Mammalian target of rapamycin; Mice

Core Tip: Iron death of nerve cells caused by iron overload is an important factor in various neurodegenerative diseases, including Alzheimer’s disease (AD). The classic mammalian target of rapamycin (mTOR) signaling pathway regulates the metabolism of iron ions by regulating transferrin receptor 1 (TFR1), thereby maintaining the intracellular iron balance. It has been shown that dexmedetomidine (Dex) inhibits the release of inflammatory factors and plays a neuroprotective role, thereby improving cognitive dysfunction in elderly rats. The Dex effectively improved hippocampal neuronal loss, cognitive dysfunction, learning and memory abilities in AD mice by regulating the mTOR-TFR1 signaling pathway to reduce iron death.