Validation experiment designed to validate causal mechanisms targeting PSEN1,APP,MAPT,CHAT in 3xAD-ChAT-Cre transgenic mice. Primary outcome: Validation of functional Cre expression in cholinergic neurons and AD pathology
This experiment involved crossbreeding 3xTg-AD mice (carrying PSEN1, APPSwe, and tauP301L mutations) with ChAT-Cre mice to create a new transgenic mouse model (3xAD-ChAT-Cre) that combines Alzheimer's disease pathology with Cre recombinase expression specifically in cholinergic neurons. The model was validated through serial genotyping to establish homozygous colonies, immunohistochemical confirmation of AD pathological hallmarks (amyloid-β plaques and phosphorylated tau aggregates), functional testing of Cre enzyme activity using DREADD virus injection and c-Fos activation, and comprehensive behavioral characterization including cognitive, motor, and anxiety-related assessments. This model enables targeted cholinergic manipulation in the context of AD pathology for mechanistic studies.
Crossbreeding of 3xTg-AD and ChAT-Cre strains, serial genotyping, establishment of homozygous colony, immunohistochemistry for Aβ and pTau, unilateral AAV8-hSyn-DIO-hM3Dq-mCherry injection into nucleus basalis magnocellularis, c-Fos activation testing with clozapine-N-oxide, behavioral testing (Y-maze, social discrimination, single pellet reaching, fox odor, splash tests), RNAscope for Cre expression validation
Functional Cre expression in ChAT-positive cells, progressive AD pathology (Aβ plaques and pTau aggregates), behavioral deficits consistent with AD phenotype including decreased locomotion, increased anxiety, and impaired fine motor skills
Homozygous expression of all four transgenes, immunohistochemical confirmation of AD pathology, functional Cre activity demonstrated by increased c-Fos in virus-injected hemisphere, behavioral alterations consistent with 3xTg-AD phenotype
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