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@ARTICLE{Cangalaya:284351,
      author       = {Cangalaya, Carla and Düsedau, Henning Peter and Dunay,
                      Ildiko Rita and Dityatev, Alexander and Stoyanov, Stoyan
                      Borislavov},
      title        = {{C}erebellar {R}esistance to {A}myloid {P}laque
                      {D}eposition and {E}levated {M}icroglial {ECM}
                      {P}roteoglycan {U}ptake in 5x{FAD} {M}ice.},
      journal      = {Cells},
      volume       = {15},
      number       = {2},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DZNE-2026-00122},
      pages        = {182},
      year         = {2026},
      abstract     = {In both Alzheimer's disease (AD) patients and animal
                      models, senile plaques are generally observed in the
                      cerebral cortex rather than the cerebellum. The mechanisms
                      underlying the regional resistance of the cerebellum to
                      amyloid plaque deposition remain poorly understood. We
                      investigated this cerebellar resistance using 5xFAD mice, an
                      amyloidosis model with high expression of mutant human APP
                      and PSEN1 in the cortex and cerebellum. In aged 5xFAD mice,
                      the cerebellum had minimal amyloid-β (Aβ) deposition
                      despite robust transgene expression, correlating with lower
                      expression levels of IBA1, CD68, TREM2, and CD36 (although
                      elevated expression of CD45 and MHC I) compared to the
                      cortex. Consistent with the absence of plaques, cerebellar
                      tissue lacked the dystrophic VGLUT1-positive synaptic
                      accumulations prominent in the cortex. Cerebellar microglia
                      maintained a distinct, less inflammatory phenotype yet
                      displayed efficient clearance activity. Notably, ASC
                      inflammasome specks-capable of seeding Aβ aggregation-were
                      paradoxically more abundant in the cerebellum, implying that
                      rapid Aβ clearance prevents these seeds from driving plaque
                      formation. Furthermore, key extracellular matrix (ECM)
                      proteoglycans brevican and aggrecan were elevated in the
                      5xFAD cerebellum. Cerebellar microglia showed enhanced
                      internalization of brevican alongside small Aβ aggregates,
                      exceeding that in cortical microglia. These findings
                      indicate that region-specific microglial and ECM
                      interactions-particularly efficient uptake and degradation
                      of ECM-Aβ co-aggregates-may underlie the cerebellum's
                      resilience to amyloid plaque pathology.},
      keywords     = {Animals / Microglia: metabolism / Microglia: pathology /
                      Plaque, Amyloid: metabolism / Plaque, Amyloid: pathology /
                      Cerebellum: metabolism / Cerebellum: pathology / Mice,
                      Transgenic / Mice / Alzheimer Disease: pathology / Alzheimer
                      Disease: metabolism / Extracellular Matrix: metabolism /
                      Proteoglycans: metabolism / Disease Models, Animal / Humans
                      / Amyloid beta-Peptides: metabolism / Cerebral Cortex:
                      metabolism / Cerebral Cortex: pathology / Alzheimer’s
                      disease (Other) / cerebellum (Other) / cortex (Other) /
                      extracellular matrix (Other) / microglia (Other) /
                      perineuronal nets (Other) / proteoglycans (Other) / synaptic
                      pruning (Other) / Proteoglycans (NLM Chemicals) / Amyloid
                      beta-Peptides (NLM Chemicals)},
      cin          = {AG Dityatev},
      ddc          = {570},
      cid          = {I:(DE-2719)1310007},
      pnm          = {351 - Brain Function (POF4-351)},
      pid          = {G:(DE-HGF)POF4-351},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41597256},
      doi          = {10.3390/cells15020182},
      url          = {https://pub.dzne.de/record/284351},
}