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000284349 1001_ $$0P:(DE-2719)2810906$$aXie, Kan$$b0$$eFirst author$$udzne
000284349 245__ $$aSelective vulnerability of the aging cholinergic system to amyloid pathology revealed by induced APP overexpression.
000284349 260__ $$aLondon$$bBioMed Central$$c2026
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000284349 520__ $$aAlzheimer'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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000284349 650_7 $$2Other$$aAging
000284349 650_7 $$2Other$$aAlzheimer´s disease
000284349 650_7 $$2Other$$aAβ
000284349 650_7 $$2Other$$aCholinergic system
000284349 650_7 $$2Other$$aNeurodegeneration
000284349 650_7 $$2NLM Chemicals$$aAmyloid beta-Protein Precursor
000284349 650_7 $$2NLM Chemicals$$aAmyloid beta-Peptides
000284349 650_2 $$2MeSH$$aAnimals
000284349 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: genetics
000284349 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: biosynthesis
000284349 650_2 $$2MeSH$$aAmyloid beta-Protein Precursor: metabolism
000284349 650_2 $$2MeSH$$aMice, Transgenic
000284349 650_2 $$2MeSH$$aMice
000284349 650_2 $$2MeSH$$aAging: pathology
000284349 650_2 $$2MeSH$$aAging: metabolism
000284349 650_2 $$2MeSH$$aAging: genetics
000284349 650_2 $$2MeSH$$aHumans
000284349 650_2 $$2MeSH$$aBrain: pathology
000284349 650_2 $$2MeSH$$aBrain: metabolism
000284349 650_2 $$2MeSH$$aAmyloid beta-Peptides: metabolism
000284349 650_2 $$2MeSH$$aAlzheimer Disease: pathology
000284349 650_2 $$2MeSH$$aAlzheimer Disease: metabolism
000284349 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000284349 650_2 $$2MeSH$$aMale
000284349 650_2 $$2MeSH$$aDisease Models, Animal
000284349 650_2 $$2MeSH$$aMice, Inbred C57BL
000284349 650_2 $$2MeSH$$aCholinergic Neurons: pathology
000284349 650_2 $$2MeSH$$aCholinergic Neurons: metabolism
000284349 7001_ $$0P:(DE-2719)2431567$$aRyan, Devon$$b1
000284349 7001_ $$0P:(DE-2719)2402373$$aSchröder, Susanne$$b2
000284349 7001_ $$0P:(DE-HGF)0$$aFreund, Lena$$b3
000284349 7001_ $$0P:(DE-2719)2810547$$aBonn, Stefan$$b4
000284349 7001_ $$0P:(DE-HGF)0$$aZhou, Yu$$b5
000284349 7001_ $$0P:(DE-2719)2289209$$aEhninger, Dan$$b6$$eLast author$$udzne
000284349 773__ $$0PERI:(DE-600)2156455-3$$a10.1186/s12974-025-03682-2$$gVol. 23, no. 1, p. 39$$n1$$p39$$tJournal of neuroinflammation$$v23$$x1742-2094$$y2026
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