TY  - JOUR
AU  - Xie, Kan
AU  - Ryan, Devon
AU  - Schröder, Susanne
AU  - Freund, Lena
AU  - Bonn, Stefan
AU  - Zhou, Yu
AU  - Ehninger, Dan
TI  - Selective vulnerability of the aging cholinergic system to amyloid pathology revealed by induced APP overexpression.
JO  - Journal of neuroinflammation
VL  - 23
IS  - 1
SN  - 1742-2094
CY  - London
PB  - BioMed Central
M1  - DZNE-2026-00120
SP  - 39
PY  - 2026
AB  - 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.
KW  - Animals
KW  - Amyloid beta-Protein Precursor: genetics
KW  - Amyloid beta-Protein Precursor: biosynthesis
KW  - Amyloid beta-Protein Precursor: metabolism
KW  - Mice, Transgenic
KW  - Mice
KW  - Aging: pathology
KW  - Aging: metabolism
KW  - Aging: genetics
KW  - Humans
KW  - Brain: pathology
KW  - Brain: metabolism
KW  - Amyloid beta-Peptides: metabolism
KW  - Alzheimer Disease: pathology
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: genetics
KW  - Male
KW  - Disease Models, Animal
KW  - Mice, Inbred C57BL
KW  - Cholinergic Neurons: pathology
KW  - Cholinergic Neurons: metabolism
KW  - Aging (Other)
KW  - Alzheimer´s disease (Other)
KW  - Aβ (Other)
KW  - Cholinergic system (Other)
KW  - Neurodegeneration (Other)
KW  - Amyloid beta-Protein Precursor (NLM Chemicals)
KW  - Amyloid beta-Peptides (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41495755
C2  - pmc:PMC12849525
DO  - DOI:10.1186/s12974-025-03682-2
UR  - https://pub.dzne.de/record/284349
ER  -