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

ARTICLE HIGHLIGHTS

Research background

The main pathological feature of Alzheimer’s disease (AD) is the formation of amyloid β-protein (Aβ) plaques in the brain, leading to loss of neuronal synapses, ultimately affecting the patient’s learning and memory abilities. Research has shown that iron death caused by iron overload in nerve cells is an important factor leading to neurodegenerative diseases, and plays a crucial role in the progression of AD. Recently, reports have demonstrated the high selectivity of dexmedetomidine (Dex), an α adrenergic receptor agonist, that can exert neuroprotective effects by inhibiting the release of inflammatory factors, thereby improving cognitive dysfunction in elderly rats.

Research motivation

Currently, there are still no effective drugs to delay the progression of AD, and iron death which may play a crucial role in the progression of this disease is attracting increasing attention from researchers.

Research objectives

To investigate the effect of Dex on iron death in the hippocampus of AD mice by both in vitro and in vivo research.

Research methods

Construction and utilization of an AD model using Aβ. The mouse hippocampal neuronal cell line HT22 was induced, and the levels of cell proliferation activity and intracellular Fe²⁺ were measured by the cell-counting kit-8 assay and immunofluorescence. The contents of malondialdehyde and glutathione were measured by the TBA method and microplate method, respectively. In the AD mouse model Aβ was injected, and the pathological damage in the mouse hippocampus was detected by hematoxylin and eosin staining and Nissl staining. The Morris water maze was used to evaluate the learning and memory abilities of mice in each group, and protein immunoblotting was used to evaluate the expression levels of p-mammalian target of rapamycin (p-mTOR) and iron death-related proteins transferrin receptor 1 (TFR1), SLC7A11, and glutathione peroxidase 4.

Research results

Dex significantly improved lipid peroxidation and iron influx in mouse hippocampal neurons (HNs) both in vivo and in vitro, and inhibition of the mTOR signaling pathway blocked this process, demonstrating that Dex can inhibit the damage caused by iron death in mouse HNs by activating mTOR-TFR1 signaling regulation, thereby improving cognitive dysfunction in AD mice.

Research conclusions

Dex can significantly activate the mTOR-TFR1 signaling pathway and inhibit iron death in mouse HNs, thereby improving the learning and memory abilities of mice.

Research perspectives

From in vitro and in vivo molecular experimental research, it is possible to analyze the effect of Dex on iron death in AD related nerve cells.