The role of NF-κB signaling pathway in reactive astrocytes among neurodegeneration after methamphetamine exposure by integrated bioinformatics

Methamphetamine (METH) is a highly addictive stimulant that has become one of the top five risk substances cause deaths from substance abuse. METH exposure increases the risk of neurodegenerative disease (ND), such as Parkinson's disease (PD), leading to disability and death. Activation of reactive astrocytes is an essential factor in neurodegeneration, and their complex role in METH exposure remains unclear. This study explored the role of reactive astrocyte overactivation in neurodegeneration after METH exposure.

This study explored the crosstalk between astrocytes and neurons in METH exposure, providing a potential pathogenesis to explore the altered immune microenvironment involving reactive astrocytes after METH exposure.

METH bulk RNA sequencing data (GSE107015 and GSE98793) and single-cell RNA sequencing data (GSE119861) were obtained from the GEO database. We performed immune infiltration analysis on the bulk RNA data. After cell clustering using the single-cell RNA data, astrocytes were extracted for downstream analysis. Differentially expressed genes (DEGs) were identified from the bulk and single-cell RNA sequencing datasets, and GO, KEGG, and GSEA pathway analyses were performed. The PPI network and random forest methods were performed on the overlapping genes of the DEGs to screen hub genes. To explore the common ground between METH exposure and neurodegenerative diseases, we applied a random forest algorithm to PD chip data (GSE99039 and GSE72267) to establish a diagnostic model using the hub genes in METH. New object recognition and the Morris water maze were used to examine cognitive function in mice exposed to METH for 14 days in vivo. Astrocytes were cocultured with neurons for the detection of intercellular crosstalk.

DEGs in the METH group significantly enriched pathways related to NDs, inflammation, and the NF-κB signaling pathway. Immune infiltration analysis revealed significantly increased infiltration of monocytes, T cells, and NK cells and decreased infiltration of neutrophils in the METH group. An intersection of 44 hub genes was screened based on the PPI network and random forest algorithm. These genes suggest that there might be similar pathogenesis between METH exposure and PD. METH exposure resulted in learning memory impairment, hippocampal astrocyte activation, and upregulation of NF-κB expression in mice. Activation of reactive astrocytes cocultured with neurons causes neural damage. Conclusions: This study explored the crosstalk between astrocytes and neurons in METH exposure, providing a potential pathogenesis to explore the altered immune microenvironment involving reactive astrocytes after METH exposure.