Pampuscenko Katryna, Jankeviciute Silvija, Morkuniene Ramune, Sulskis Darius, Smirnovas Vytautas, Brown Guy C, Borutaite Vilmante
Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania.
Life Sciences Center, Institute of Biotechnology, Vilnius University, LT-10257 Vilnius, Lithuania.
Neurobiol Dis. 2025 Mar;206:106817. doi: 10.1016/j.nbd.2025.106817. Epub 2025 Jan 28.
S100 calcium-binding protein A9 (S100A9, also known as calgranulin B) is expressed and secreted by myeloid cells under inflammatory conditions, and S100A9 can amplify inflammation. There is a large increase in S100A9 expression in the brains of patients with neurodegenerative diseases, such as Alzheimer's disease, and S100A9 has been suggested to contribute to neurodegeneration, but the mechanisms are unclear. Here we investigated the effects of extracellular recombinant S100A9 protein on microglia, neurons and synapses in primary rat brain neuronal-glial cell cultures. Incubation of cell cultures with 250-500 nM S100A9 caused neuronal loss without signs of apoptosis or necrosis, but accompanied by exposure of the "eat-me" signal - phosphatidylserine on neurons. S100A9 caused activation of microglial inflammation as evidenced by an increase in the microglial number, morphological changes, release of pro-inflammatory cytokines, and increased phagocytic activity. At lower concentrations, 10-100 nM S100A9 induced synaptic loss in the cultures. Depletion of microglia from the cultures prevented S100A9-induced neuronal and synaptic loss, indicating that neuronal and synaptic loss was mediated by microglia. These results suggest that extracellular S100A9 may contribute to neurodegeneration by activating microglial inflammation and phagocytosis, resulting in loss of synapses and neurons. This further suggests the possibility that neurodegeneration may be reduced by targeting S100A9 or microglia.
S100钙结合蛋白A9（S100A9，也称为钙粒蛋白B）在炎症条件下由髓样细胞表达并分泌，且S100A9可放大炎症反应。在神经退行性疾病患者（如阿尔茨海默病患者）的大脑中，S100A9表达大幅增加，有人认为S100A9会导致神经退行性变，但其机制尚不清楚。在此，我们研究了细胞外重组S100A9蛋白对原代大鼠脑神经元-神经胶质细胞培养物中的小胶质细胞、神经元和突触的影响。用250 - 500 nM的S100A9孵育细胞培养物会导致神经元丢失，且无凋亡或坏死迹象，但伴有神经元上“吃我”信号——磷脂酰丝氨酸的暴露。S100A9导致小胶质细胞炎症激活，表现为小胶质细胞数量增加、形态变化、促炎细胞因子释放以及吞噬活性增强。在较低浓度下，10 - 100 nM的S100A9可诱导培养物中的突触丢失。从培养物中去除小胶质细胞可防止S100A9诱导的神经元和突触丢失，这表明神经元和突触丢失是由小胶质细胞介导的。这些结果表明，细胞外S100A9可能通过激活小胶质细胞炎症和吞噬作用导致神经退行性变，从而导致突触和神经元丢失。这进一步提示了通过靶向S100A9或小胶质细胞来减少神经退行性变的可能性。
