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@ARTICLE{Dsedau:279879,
      author       = {Düsedau, Henning Peter and Cangalaya, Carla and Stoyanov,
                      Stoyan Borislavov and Dityatev, Alexander and Dunay, Ildiko
                      Rita},
      title        = {{R}educed synaptic tagging by complement protein {C}3 is
                      associated with elevated extracellular matrix in the
                      middle-aged cerebellum of mice.},
      journal      = {Frontiers in aging neuroscience},
      volume       = {17},
      issn         = {1663-4365},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {DZNE-2025-00846},
      pages        = {1616390},
      year         = {2025},
      abstract     = {Aging 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.In 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.We 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.The 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.},
      keywords     = {aging (Other) / cerebellum (Other) / complement system
                      (Other) / extracellular matrix (Other) / microglia (Other) /
                      proteoglycans (Other) / synaptic pruning (Other) /
                      synaptosomes (Other)},
      cin          = {AG Dityatev},
      ddc          = {610},
      cid          = {I:(DE-2719)1310007},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40641620},
      pmc          = {pmc:PMC12240999},
      doi          = {10.3389/fnagi.2025.1616390},
      url          = {https://pub.dzne.de/record/279879},
}