Stavrovskaya A V, Voronkov D N, Pavlova A K, Olshanskiy A S, Belugin B V, Ivanova M V, Zakharova M N, Illarioshkin S N
Research Center of neurology, Ministry of Science and Higher Education of the Russian Federation, Moscow, 125367 Russian Federation.
National Research Center for Epidemiology and Microbiology named after the honorary academician N. F. Gamaleya, Moscow, 123098 Russian Federation.
Acta Naturae. 2024 Oct-Dec;16(4):73-80. doi: 10.32607/actanaturae.27499.
Amyotrophic lateral sclerosis (ALS) is a severe disease of the central nervous system (CNS) characterized by motor neuron damage leading to death from respiratory failure. The neurodegenerative process in ALS is characterized by an accumulation of aberrant proteins (TDP-43, SOD1, etc.) in CNS cells. The trans-synaptic transmission of these proteins via exosomes may be one of the mechanisms through which the pathology progresses. The aim of this work was to study the effect of an intraventricular injection of exosomes obtained from the cerebrospinal fluid (CSF) of ALS patients on the motor activity and CNS pathomorphology of mice. The exosomes were obtained from two ALS patients and a healthy donor. Exosome suspensions at high and low concentrations were injected into the lateral brain ventricles of male BALB/c mice ( = 45). Motor activity and physiological parameters were evaluated twice a month; morphological examination of the spinal cord was performed 14 months after the start of the experiment. Nine months after administration of exosomes from the ALS patients, the animals started exhibiting a pathological motor phenotype; i.e., altered locomotion with paresis of hind limbs, coordination impairment, and increasing episodes of immobility. The motor symptoms accelerated after administration of a higher concentration of exosomes. The experimental group showed a significant decrease in motor neuron density in the ventral horns of the spinal cord, a significant increase in the number of microglial cells, and microglia activation. The TDP43 protein in the control animals was localized in the nuclei of motor neurons. TDP43 mislocation with its accumulation in the cytoplasm was observed in the experimental group. Thus, the triggering effect of the exosomal proteins derived from the CSF of ALS patients in the development of a motor neuron pathology in the experimental animals was established. This confirms the pathogenetic role of exosomes in neurodegenerative progression and makes it possible to identify a new target for ALS therapy.
肌萎缩侧索硬化症（ALS）是一种严重的中枢神经系统（CNS）疾病，其特征是运动神经元受损，最终因呼吸衰竭而死亡。ALS的神经退行性过程的特点是中枢神经系统细胞中异常蛋白质（TDP-43、SOD1等）的积累。这些蛋白质通过外泌体的跨突触传递可能是病理进展的机制之一。这项工作的目的是研究脑室内注射从ALS患者脑脊液（CSF）中获得的外泌体对小鼠运动活动和中枢神经系统病理形态学的影响。外泌体取自两名ALS患者和一名健康供体。将高浓度和低浓度的外泌体悬浮液注射到雄性BALB/c小鼠（n = 45）的侧脑室中。每月评估两次运动活动和生理参数；在实验开始14个月后对脊髓进行形态学检查。在注射来自ALS患者的外泌体九个月后，动物开始表现出病理性运动表型；即运动改变，伴有后肢麻痹、协调障碍和不动发作增加。注射更高浓度的外泌体后，运动症状加速。实验组脊髓腹角运动神经元密度显著降低，小胶质细胞数量显著增加，且小胶质细胞活化。对照动物中的TDP43蛋白定位于运动神经元的细胞核中。在实验组中观察到TDP43错位并在细胞质中积累。因此，确定了来自ALS患者脑脊液的外泌体蛋白在实验动物运动神经元病理发展中的触发作用。这证实了外泌体在神经退行性进展中的致病作用，并有可能确定ALS治疗的新靶点。
