The study on cuproptosis in Alzheimer's disease based on the cuproptosis key gene .

BACKGROUND

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory and cognitive impairments. Previous studies have shown neuronal death in the brains of AD patients, but the role of cuproptosis and its associated genes in AD neurons remains unclear.

METHODS

Intersection analysis was conducted using the AD transcriptome dataset GSE63060, neuron dataset GSE147528, and reported cuproptosis-related genes to identify the cuproptosis key gene highly expressed in AD. Subsequently, cell experiments were performed by treating SH-SY5Y cells with Aβ to establish AD cell model. The real-time reverse transcriptase-polymerase chain reaction (RT-qPCR) and western blotting (WB) assays were employed to detect the expression levels of , , and . Cell proliferation was analyzed by counting Kit-8 (CCK8), mitochondrial ROS levels were analyzed using flow cytometry. shRNA was used to downregulate expression, followed by repetition of the aforementioned experiments. Clinical experiments utilized qPCR to detect mRNA levels in peripheral venous blood of patients, and analyzed expression differences in different genotypes of AD patients. Finally, a protein-protein interaction (PPI) network of was constructed based on the GeneMANIA database, immune infiltration analysis was conducted using R language, and transcription factors prediction for was performed based on the ENCODE database.

RESULTS

The cuproptosis key gene showed significantly higher expression in peripheral blood and neuron models of AD compared to non-AD individuals, with significantly higher expression in genotype than other genotype of AD patients. Knockdown of expression reduced the lipidation levels of and in neurons, alleviated ROS accumulation in mitochondria, improved cell viability, and mitigated cuproptosis. Immune infiltration analysis results indicated a high enrichment of peripheral blood γδ-T lymphocytes in AD, and was significantly associated with the infiltration of four immune cells and may be regulated by three transcription factors.

CONCLUSION

The cuproptosis key gene is highly expressed in AD and may promote cuproptosis in AD neurons by regulating the lipidation levels of and , thereby participating in the onset and development of AD. This provides a potential target for the diagnosis and treatment of AD.