284349 20260212105835.0 10.1186/s12974-025-03682-2 doi pmid:41495755 pmid pmc:PMC12849525 pmc DZNE-2026-00120 English 610 Xie, Kan P:(DE-2719)2810906 0 First author dzne Selective vulnerability of the aging cholinergic system to amyloid pathology revealed by induced APP overexpression. London 2026 BioMed Central article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1770812277_18491 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote 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. 352 - Disease Mechanisms (POF4-352) G:(DE-HGF)POF4-352 POF4-352 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de Aging Other Alzheimer´s disease Other Aβ Other Cholinergic system Other Neurodegeneration Other Amyloid beta-Protein Precursor NLM Chemicals Amyloid beta-Peptides NLM Chemicals Animals MeSH Amyloid beta-Protein Precursor: genetics MeSH Amyloid beta-Protein Precursor: biosynthesis MeSH Amyloid beta-Protein Precursor: metabolism MeSH Mice, Transgenic MeSH Mice MeSH Aging: pathology MeSH Aging: metabolism MeSH Aging: genetics MeSH Humans MeSH Brain: pathology MeSH Brain: metabolism MeSH Amyloid beta-Peptides: metabolism MeSH Alzheimer Disease: pathology MeSH Alzheimer Disease: metabolism MeSH Alzheimer Disease: genetics MeSH Male MeSH Disease Models, Animal MeSH Mice, Inbred C57BL MeSH Cholinergic Neurons: pathology MeSH Cholinergic Neurons: metabolism MeSH Ryan, Devon P:(DE-2719)2431567 1 Schröder, Susanne P:(DE-2719)2402373 2 Freund, Lena P:(DE-HGF)0 3 Bonn, Stefan P:(DE-2719)2810547 4 Zhou, Yu P:(DE-HGF)0 5 Ehninger, Dan P:(DE-2719)2289209 6 Last author dzne 10.1186/s12974-025-03682-2 Vol. 23, no. 1, p. 39 PERI:(DE-600)2156455-3 1 39 Journal of neuroinflammation 23 2026 1742-2094 http://pub.dzne.de/record/284349/files/DZNE-2026-00120%20SUP.zip OpenAccess http://pub.dzne.de/record/284349/files/DZNE-2026-00120.pdf OpenAccess pdfa http://pub.dzne.de/record/284349/files/DZNE-2026-00120.pdf?subformat=pdfa oai:pub.dzne.de:284349 openaire open_access VDB driver dnbdelivery Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 0 P:(DE-2719)2810906 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 1 P:(DE-2719)2431567 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 2 P:(DE-2719)2402373 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 3 P:(DE-HGF)0 Deutsches Zentrum für Neurodegenerative Erkrankungen I:(DE-588)1065079516 DZNE 6 P:(DE-2719)2289209 DE-HGF Gesundheit Neurodegenerative Diseases G:(DE-HGF)POF4-350 G:(DE-HGF)POF4-352 G:(DE-HGF)POF4 G:(DE-HGF)POF4-300 G:(DE-HGF)POF Disease Mechanisms 0 2026 DBCoverage StatID:(DE-HGF)0200 StatID SCOPUS 2024-12-16 DBCoverage StatID:(DE-HGF)0160 StatID Essential Science Indicators 2024-12-16 DBCoverage StatID:(DE-HGF)1050 StatID BIOSIS Previews 2024-12-16 DBCoverage StatID:(DE-HGF)1190 StatID Biological Abstracts 2024-12-16 DBCoverage StatID:(DE-HGF)0600 StatID Ebsco Academic Search 2024-12-16 OpenAccess StatID:(DE-HGF)0510 StatID JCR StatID:(DE-HGF)0100 StatID J NEUROINFLAMM : 2022 2024-12-16 DBCoverage StatID:(DE-HGF)0501 StatID DOAJ Seal 2024-04-10T15:42:04Z DBCoverage StatID:(DE-HGF)0500 StatID DOAJ 2024-04-10T15:42:04Z DBCoverage StatID:(DE-HGF)1030 StatID Current Contents - Life Sciences 2024-12-16 Fees StatID:(DE-HGF)0700 StatID 2024-12-16 DBCoverage StatID:(DE-HGF)0150 StatID Web of Science Core Collection 2024-12-16 WoS StatID:(DE-HGF)0113 StatID Science Citation Index Expanded 2024-12-16 Peer Review StatID:(DE-HGF)0030 StatID ASC 2024-12-16 Article Processing Charges StatID:(DE-HGF)0561 StatID 2024-12-16 IF >= 5 StatID:(DE-HGF)9905 StatID J NEUROINFLAMM : 2022 2024-12-16 DBCoverage StatID:(DE-HGF)0300 StatID Medline 2024-12-16 Creative Commons Attribution CC BY 4.0 LIC:(DE-HGF)CCBY4 HGFVOC DBCoverage StatID:(DE-HGF)0199 StatID Clarivate Analytics Master Journal List 2024-12-16 I:(DE-2719)1013005 AG Ehninger Translational Biogerontology 0 journal VDB UNRESTRICTED I:(DE-2719)1013005 FullTexts