Journal Article

DZNE-2026-00120

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Selective vulnerability of the aging cholinergic system to amyloid pathology revealed by induced APP overexpression.

Xie, K. (First author)DZNE* ; Ryan, D.DZNE* ; Schröder, S.DZNE* ; Freund, L.DZNE* ; Bonn, S. ; Zhou, Y. ; Ehninger, D. (Last author)DZNE*

2026
BioMed Central London

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Please use a persistent id in citations: doi:10.1186/s12974-025-03682-2

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.

Keyword(s): 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) ; Aging ; Alzheimer´s disease ; Aβ ; Cholinergic system ; Neurodegeneration ; Amyloid beta-Protein Precursor ; Amyloid beta-Peptides

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Contributing Institute(s):

1. Translational Biogerontology (AG Ehninger)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2026

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