Investigating Neuroplasticity Changes Reflected by BDNF Levels in Astrocyte-Derived Extracellular Vesicles in Patients with Depression

Purpose: To investigate the neuroplasticity hypothesis of depression by measuring brain-derived neurotrophic factor (BDNF) levels in plasma astrocyte-derived extracellular vesicles (ADEVs) and to evaluate their potential as biomarkers for depression compared with Patients and Methods: Thirty-five patients with major depressive disorder (MDD) and 35 matched healthy controls (HCs) were enrolled. Plasma ADEVs were isolated using a combination of ultracentrifugation and immunoaffinity capture. Isolated ADEVs were validated using transmission electron microscopy, nanoparticle tracking analysis, and Western blotting. BDNF levels were quantified in both ADEVs and plasma. ALG-2-interacting protein X (Alix) and cluster of differentiation 81 (CD81) levels, two established extracellular vesicle markers, were measured in ADEVs. Results: After false discovery rate correction, patients with MDD exhibited higher CD81 levels (PFDR = 0.040) and lower BDNF levels (PFDR = 0.043) in ADEVs than HCs at baseline. BDNF levels in ADEVs normalized to CD81 (PFDR = 0.002) and Alix (PFDR = 0.040) remained consistent with this finding. Following four weeks of selective serotonin reuptake inhibitor treatment (n=10), CD81 levels in ADEVs decreased (PFDR = 0.046), while BDNF levels normalized to CD81 increased (PFDR = 0.022). BDNF levels in ADEVs were more stable than in plasma. Exploratory analysis revealed no correlation between BDNF levels in ADEVs and plasma (rho=0.117, P = 0.334). Conclusion: This study provides human in vivo evidence supporting the neuroplasticity hypothesis of depression by demonstrating altered BDNF levels in ADEVs. ADEVs may be more suitable for developing biomarkers of depression than plasma-derived biomarkers.