Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice
BackgroundAging of the brain is associated with cognitive decline and recognized as a major risk factor for the development of neurodegenerative diseases. On a cellular level, brain aging is accompanied by a progressive increase of the basal pro-inflammatory tonus, leading to the activation of phago...
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Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Aging Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1616390/full |
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| author | Henning Peter Düsedau Carla Cangalaya Stoyan Stoyanov Alexander Dityatev Alexander Dityatev Alexander Dityatev Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay |
| author_facet | Henning Peter Düsedau Carla Cangalaya Stoyan Stoyanov Alexander Dityatev Alexander Dityatev Alexander Dityatev Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay |
| author_sort | Henning Peter Düsedau |
| collection | DOAJ |
| description | BackgroundAging of the brain is associated with cognitive decline and recognized as a major risk factor for the development of neurodegenerative diseases. On a cellular level, brain aging is accompanied by a progressive increase of the basal pro-inflammatory tonus, leading to the activation of phagocytic pathways in brain-resident microglia and disruptive effects on synaptic neurotransmission. While the aging process affects all brain compartments at different velocities and one of the particularly affected regions is the cerebellum (CB), the underlying effects remain elusive.MethodsIn the present study, we harnessed a murine model of natural aging in males combined with orthogonal experimental approaches comprising of cytokine gene expression analysis, flow cytometry, immunohistochemistry, and flow synaptometry.ResultsWe report age-dependent morphological and phenotypic changes in microglia that are distinct in the cortex (CTX) and CB. Furthermore, we show an increased expression of cytokines and complement factors upon aging and a decline of C3-tagged VGLUT1+ presynaptic puncta in the CB. Using flow synaptometry to quantify the composition of synapses in more detail, we validated the reduction of C3b-labeled excitatory synaptosomes while the overall frequency of glutamatergic synaptosomes remained unaffected by aging. Notably, proteoglycans brevican and aggrecan, key components of the neural extracellular matrix, were significantly upregulated in the middle-aged CB.DiscussionThe data presented herein suggests the ECM-mediated shielding of synapses from complement-tagging and subsequent engulfment by microglia. Thus, we provide novel insights into mechanisms that may confer resilience in the brain by modulating synapse removal in the context of aging. |
| format | Article |
| id | doaj-art-783ae2c654bc482e9cf6a19503d5bfc6 |
| institution | Kabale University |
| issn | 1663-4365 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Aging Neuroscience |
| spelling | doaj-art-783ae2c654bc482e9cf6a19503d5bfc62025-08-20T03:27:51ZengFrontiers Media S.A.Frontiers in Aging Neuroscience1663-43652025-06-011710.3389/fnagi.2025.16163901616390Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of miceHenning Peter Düsedau0Carla Cangalaya1Stoyan Stoyanov2Alexander Dityatev3Alexander Dityatev4Alexander Dityatev5Ildiko Rita Dunay6Ildiko Rita Dunay7Ildiko Rita Dunay8Ildiko Rita Dunay9Ildiko Rita Dunay10Institute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-von-Guericke-University, Magdeburg, GermanyMolecular Neuroplasticity Research Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, GermanyMolecular Neuroplasticity Research Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, GermanyMolecular Neuroplasticity Research Group, German Center for Neurodegenerative Diseases (DZNE), Magdeburg, GermanyCenter for Behavioral Brain Sciences (CBBS), Magdeburg, GermanyMedical Faculty, Otto-von-Guericke-University, Magdeburg, GermanyInstitute of Inflammation and Neurodegeneration, Health Campus Immunology, Infectiology and Inflammation (GC-I3), Otto-von-Guericke-University, Magdeburg, GermanyCenter for Behavioral Brain Sciences (CBBS), Magdeburg, GermanyMedical Faculty, Otto-von-Guericke-University, Magdeburg, GermanyGerman Center for Mental Health (DZPG), Magdeburg, GermanyCenter for Intervention and Research on Adaptive and Maladaptive Brain Circuits Underlying Mental Health (C-I-R-C), Halle-Jena-Magdeburg, GermanyBackgroundAging of the brain is associated with cognitive decline and recognized as a major risk factor for the development of neurodegenerative diseases. On a cellular level, brain aging is accompanied by a progressive increase of the basal pro-inflammatory tonus, leading to the activation of phagocytic pathways in brain-resident microglia and disruptive effects on synaptic neurotransmission. While the aging process affects all brain compartments at different velocities and one of the particularly affected regions is the cerebellum (CB), the underlying effects remain elusive.MethodsIn the present study, we harnessed a murine model of natural aging in males combined with orthogonal experimental approaches comprising of cytokine gene expression analysis, flow cytometry, immunohistochemistry, and flow synaptometry.ResultsWe report age-dependent morphological and phenotypic changes in microglia that are distinct in the cortex (CTX) and CB. Furthermore, we show an increased expression of cytokines and complement factors upon aging and a decline of C3-tagged VGLUT1+ presynaptic puncta in the CB. Using flow synaptometry to quantify the composition of synapses in more detail, we validated the reduction of C3b-labeled excitatory synaptosomes while the overall frequency of glutamatergic synaptosomes remained unaffected by aging. Notably, proteoglycans brevican and aggrecan, key components of the neural extracellular matrix, were significantly upregulated in the middle-aged CB.DiscussionThe data presented herein suggests the ECM-mediated shielding of synapses from complement-tagging and subsequent engulfment by microglia. Thus, we provide novel insights into mechanisms that may confer resilience in the brain by modulating synapse removal in the context of aging.https://www.frontiersin.org/articles/10.3389/fnagi.2025.1616390/fullextracellular matrixproteoglycansagingmicrogliacerebellumcomplement system |
| spellingShingle | Henning Peter Düsedau Carla Cangalaya Stoyan Stoyanov Alexander Dityatev Alexander Dityatev Alexander Dityatev Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Ildiko Rita Dunay Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice Frontiers in Aging Neuroscience extracellular matrix proteoglycans aging microglia cerebellum complement system |
| title | Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice |
| title_full | Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice |
| title_fullStr | Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice |
| title_full_unstemmed | Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice |
| title_short | Reduced synaptic tagging by complement protein C3 is associated with elevated extracellular matrix in the middle-aged cerebellum of mice |
| title_sort | reduced synaptic tagging by complement protein c3 is associated with elevated extracellular matrix in the middle aged cerebellum of mice |
| topic | extracellular matrix proteoglycans aging microglia cerebellum complement system |
| url | https://www.frontiersin.org/articles/10.3389/fnagi.2025.1616390/full |
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