Epidermal Growth Factor in the Brain: A Promising Biomarker for Depression

BackgroundThis study aimed to examine the neurotrophic factors secreted from brain in depression by analyzing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma, and to explore the causal relationship between the expression of neurotrophic factors in the brain and depression. MethodsA total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls (HCs) were recruited at baseline, and 34 TRD patients completed the post-electroconvulsive therapy (ECT) visits. The concentrations of five neurotrophic factors in ADEVs were measured. A correlation analysis was performed between neurotrophic factors in ADEVs and neurogenesis marker doublecortin (DCX) in neuron-derived extracellular vesicles (NDEVs). Subsequently, Mendelian randomization (MR) study and cell experiments were conducted. ResultsOur findings revealed a decrease in the level of epidermal growth factor (EGF) in ADEVs among TRD patients, with an increase observed post-ECT. The corrected area under the curve for EGF were larger than those for other neurotrophic factors: 0.99 (95% CI: 0.98-1.00). MR suggested that decreased expression levels of the EGF gene in the cortex constitute a risk factor for depression. We observed a positive correlation between the levels of EGF in ADEVs and DCX in NDEVs. Subsequently, cell experiments suggested that EGF can activate EGF receptor (EGFR) to trigger the PI3K-Akt pathway, participating in the promotion of DCX. ConclusionsThis study provides the in vivo evidences supporting that a reduction in EGF levels in the central nervous system could potentially contribute to depression and serve as a biomarker for it. Additionally, the EGF/EGFR signaling pathway may be involved in regulating early neurogenesis traits in depression.