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001     284349
005     20260212105835.0
024 7 _ |a 10.1186/s12974-025-03682-2
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082 _ _ |a 610
100 1 _ |a Xie, Kan
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245 _ _ |a Selective vulnerability of the aging cholinergic system to amyloid pathology revealed by induced APP overexpression.
260 _ _ |a London
|c 2026
|b BioMed Central
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520 _ _ |a 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.
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650 _ 7 |a Aging
|2 Other
650 _ 7 |a Alzheimer´s disease
|2 Other
650 _ 7 |a Aβ
|2 Other
650 _ 7 |a Cholinergic system
|2 Other
650 _ 7 |a Neurodegeneration
|2 Other
650 _ 7 |a Amyloid beta-Protein Precursor
|2 NLM Chemicals
650 _ 7 |a Amyloid beta-Peptides
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: genetics
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: biosynthesis
|2 MeSH
650 _ 2 |a Amyloid beta-Protein Precursor: metabolism
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Aging: pathology
|2 MeSH
650 _ 2 |a Aging: metabolism
|2 MeSH
650 _ 2 |a Aging: genetics
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Brain: pathology
|2 MeSH
650 _ 2 |a Brain: metabolism
|2 MeSH
650 _ 2 |a Amyloid beta-Peptides: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: pathology
|2 MeSH
650 _ 2 |a Alzheimer Disease: metabolism
|2 MeSH
650 _ 2 |a Alzheimer Disease: genetics
|2 MeSH
650 _ 2 |a Male
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Cholinergic Neurons: pathology
|2 MeSH
650 _ 2 |a Cholinergic Neurons: metabolism
|2 MeSH
700 1 _ |a Ryan, Devon
|0 P:(DE-2719)2431567
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700 1 _ |a Schröder, Susanne
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700 1 _ |a Freund, Lena
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700 1 _ |a Bonn, Stefan
|0 P:(DE-2719)2810547
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700 1 _ |a Zhou, Yu
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700 1 _ |a Ehninger, Dan
|0 P:(DE-2719)2289209
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773 _ _ |a 10.1186/s12974-025-03682-2
|g Vol. 23, no. 1, p. 39
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|t Journal of neuroinflammation
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|y 2026
|x 1742-2094
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