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@ARTICLE{Xie:284349,
      author       = {Xie, Kan and Ryan, Devon and Schröder, Susanne and Freund,
                      Lena and Bonn, Stefan and Zhou, Yu and Ehninger, Dan},
      title        = {{S}elective vulnerability of the aging cholinergic system
                      to amyloid pathology revealed by induced {APP}
                      overexpression.},
      journal      = {Journal of neuroinflammation},
      volume       = {23},
      number       = {1},
      issn         = {1742-2094},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {DZNE-2026-00120},
      pages        = {39},
      year         = {2026},
      abstract     = {Alzheimer's disease (AD) is a progressive neurodegenerative
                      disorder characterized by amyloid beta (Aβ) accumulation,
                      tau pathology, and cognitive decline, with aging as the
                      primary risk factor. To investigate whether age influences
                      susceptibility to Aβ toxicity, we used a
                      tetracycline-inducible mouse model expressing a mutant human
                      APP transgene (APPSweInd) and initiated expression during
                      either mid-age (6-18 months) or old age (12-24 months).
                      After one year of transgene activation, we assessed
                      behavior, amyloid pathology, inflammation, autophagy, and
                      brain gene expression compared to age-matched controls.
                      Although APP expression, Aβ deposition, inflammatory
                      markers, and autophagic flux were comparable between age
                      groups, aged APP-expressing mice displayed cognitive
                      impairments, hyperactivity, and motor deficits that were
                      absent in their younger counterparts. Transcriptomic
                      analysis revealed selective downregulation of cholinergic
                      system genes specifically in the aged APP-induced group,
                      validated at RNA and protein levels. No changes were
                      observed in markers of other neuronal cell types, indicating
                      a targeted cholinergic vulnerability. These findings suggest
                      that age enhances the brain's susceptibility to Aβ
                      toxicity, particularly affecting the cholinergic system,
                      rather than amplifying amyloid burden itself. This inducible
                      model provides a relevant platform to study the interaction
                      between aging and Aβ pathology and may help identify
                      age-related factors contributing to AD progression.},
      keywords     = {Animals / Amyloid beta-Protein Precursor: genetics /
                      Amyloid beta-Protein Precursor: biosynthesis / Amyloid
                      beta-Protein Precursor: metabolism / Mice, Transgenic / Mice
                      / Aging: pathology / Aging: metabolism / Aging: genetics /
                      Humans / Brain: pathology / Brain: metabolism / Amyloid
                      beta-Peptides: metabolism / Alzheimer Disease: pathology /
                      Alzheimer Disease: metabolism / Alzheimer Disease: genetics
                      / Male / Disease Models, Animal / Mice, Inbred C57BL /
                      Cholinergic Neurons: pathology / Cholinergic Neurons:
                      metabolism / Aging (Other) / Alzheimer´s disease (Other) /
                      Aβ (Other) / Cholinergic system (Other) / Neurodegeneration
                      (Other) / Amyloid beta-Protein Precursor (NLM Chemicals) /
                      Amyloid beta-Peptides (NLM Chemicals)},
      cin          = {AG Ehninger},
      ddc          = {610},
      cid          = {I:(DE-2719)1013005},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41495755},
      pmc          = {pmc:PMC12849525},
      doi          = {10.1186/s12974-025-03682-2},
      url          = {https://pub.dzne.de/record/284349},
}