Pagliarini Marica, Guidi Loretta, Ciacci Caterina, Saltarelli Roberta, Orciani Monia, Martino Marianna, Albertini Maria Cristina, Arnaldi Giorgio, Ambrogini Patrizia
Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029, Urbino, Italy.
Department of Neurology, Ulm University, 89081, Ulm, Germany.
Mol Neurobiol. 2025 May 24. doi: 10.1007/s12035-025-05069-z.
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.
海马体是大脑中糖皮质激素（GCs）的主要作用靶点，因为它含有浓度最高的特异性受体。GCs是调节成年海马体神经发生（AHN）的因素之一，AHN发生在包括人类在内的哺乳动物中。长期暴露于高GC水平会引发AHN损伤，并导致情感和认知缺陷，这与海马体神经发生的功能一致。库欣综合征（CS）是一种罕见的内分泌疾病，其特征是GC水平持续升高，即皮质醇水平升高，这也会导致情感障碍和海马体相关记忆受损，提示海马体神经发生受到破坏。成年神经发生过程中的参与者，如神经干/祖细胞和正在分化的神经元细胞，会释放能够穿过血脑屏障并进入外周血的外泌体。已知微小RNA在神经元外泌体中选择性富集，并在成年神经发生调节中发挥关键作用。这项探索性研究的主要问题是，外周血中神经元衍生外泌体携带的与神经可塑性相关的微小RNA（miRNAs）是否能反映与库欣综合征相关的神经发生过程的改变。因此，在本研究中，我们测量了内源性和活动性CS患者以及年龄和性别匹配的健康受试者外周血中神经元衍生外泌体中选定miRNAs的含量。通过逆转录定量聚合酶链反应（RT-qPCR）对人类miRNAs（miR-126、miR-9、miR-223、miR-34a、miR-124a和miR-146a）进行定量分析。与健康受试者相比，所有分析的miRNAs在CS患者中均有显著差异表达。我们的研究结果支持以下观点：（i）库欣综合征（CS）患者可能存在神经发生的假定失调，这可能是情感和认知功能早期受损的基础；（ii）外泌体货物可能是监测成年人类功能性和功能失调性神经可塑性过程的潜在生物标志物。需要更多的研究来在更广泛的患者队列中证实并扩展这些发现。
