Circulating Neuronal Exosome Cargo as Biomarkers of Neuroplasticity in Cushing’s Syndrome

The hippocampus is the main target of glucocorticoids (GCs) in the brain since it contains the greatest concentration of the specific receptors. GCs are among the factors modulating adult hippocampal neurogenesis (AHN), which occurs in mammalians, including humans. Prolonged exposure to high GC levels triggers AHN impairment and induces affective and cognitive deficits, consistently with hippocampal neurogenesis functions. Cushing's syndrome (CS) is a rare endocrine disorder characterized by persistently elevated GC levels, namely, cortisol, that also results in affective disorders and impairment of hippocampus-associated memory, suggesting a disruption of hippocampal neurogenesis. Players of adult neurogenesis process, such as Neural Stem/Progenitor Cells and differentiating neuronal cells, release exosomes able to cross brain blood barrier, reaching the peripheral blood. MicroRNAs are known to be selectively enriched in neuronal exosomes and to play a crucial role in adult neurogenesis regulation. The main question addressed in this exploratory study was whether neuroplasticity-related microRNAs (miRNAs), carried by neuronal-derived exosomes in peripheral blood, could reflect alterations in neurogenic processes associated with Cushing's syndrome. Hence, in the present work, we measured the content in selected miRNAs of neuronally derived exosomes in peripheral blood of patients affected by endogenous and active CS and age and sex-matched healthy subjects. The human miRNAs (miR-126, miR-9, miR-223, miR-34a, miR-124a, and miR-146a) were quantified by RT-qPCR. All the miRNAs analyzed were significantly differentially expressed in CS patients as compared to healthy subjects. Our findings support the following: (i) patients with Cushing's syndrome (CS) may exhibit a putative dysregulation of neurogenesis that could underlie the early-onset impairment of affective and cognitive functions; (ii) the exosomal cargo may represent a potential biomarker for monitoring functional and dysfunctional neuroplasticity processes in adult humans. Additional studies are needed to confirm and expand upon the findings across a wider cohort of patients.