S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss
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 Alzhe...
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| Format: | Article |
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Elsevier
2025-03-01
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| Series: | Neurobiology of Disease |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996125000336 |
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| author | Katryna Pampuscenko Silvija Jankeviciute Ramune Morkuniene Darius Sulskis Vytautas Smirnovas Guy C. Brown Vilmante Borutaite |
| author_facet | Katryna Pampuscenko Silvija Jankeviciute Ramune Morkuniene Darius Sulskis Vytautas Smirnovas Guy C. Brown Vilmante Borutaite |
| author_sort | Katryna Pampuscenko |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-8e1c122c7e984f8284cbda6fbd7d678e |
| institution | Kabale University |
| issn | 1095-953X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj-art-8e1c122c7e984f8284cbda6fbd7d678e2025-02-05T04:31:08ZengElsevierNeurobiology of Disease1095-953X2025-03-01206106817S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal lossKatryna Pampuscenko0Silvija Jankeviciute1Ramune Morkuniene2Darius Sulskis3Vytautas Smirnovas4Guy C. Brown5Vilmante Borutaite6Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; Corresponding author.Neuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, LithuaniaNeuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, LithuaniaLife Sciences Center, Institute of Biotechnology, Vilnius University, LT-10257 Vilnius, LithuaniaLife Sciences Center, Institute of Biotechnology, Vilnius University, LT-10257 Vilnius, LithuaniaDepartment of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United KingdomNeuroscience Institute, Lithuanian University of Health Sciences, LT-50161 Kaunas, LithuaniaS100 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.http://www.sciencedirect.com/science/article/pii/S0969996125000336S100A9 proteinCell deathNeurotoxicityNeuroinflammationMicrogliaNeurodegeneration |
| spellingShingle | Katryna Pampuscenko Silvija Jankeviciute Ramune Morkuniene Darius Sulskis Vytautas Smirnovas Guy C. Brown Vilmante Borutaite S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss Neurobiology of Disease S100A9 protein Cell death Neurotoxicity Neuroinflammation Microglia Neurodegeneration |
| title | S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss |
| title_full | S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss |
| title_fullStr | S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss |
| title_full_unstemmed | S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss |
| title_short | S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss |
| title_sort | s100a9 protein activates microglia and stimulates phagocytosis resulting in synaptic and neuronal loss |
| topic | S100A9 protein Cell death Neurotoxicity Neuroinflammation Microglia Neurodegeneration |
| url | http://www.sciencedirect.com/science/article/pii/S0969996125000336 |
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