The modulatory role of early-life experiences and sex on cognitive resilience in APP/PS1 mice over time
Abstract
Background
Cognitive resilience to Alzheimer’s disease (AD) can be modelled in amyloid-expressing rodents through early handling (EH). This study investigated how EH and sex affect cognition and pathology over time.
Methods
We assessed cognition (open field, object recognition test, Barnes maze) in 6- and 12-month-old APP/PS1 and WT mice (N=180, EH/Ctrl×M/F), performed biochemical and histological analyses of several brain areas to assess effects on Aβ, glial cells, and other markers of pathology, and investigated how behavior correlates with pathology.
Results
EH improved non-spatial memory at 6 months, consistent with a reduction of hippocampal microglia density, and normalized locomotor activity at 12 months (both p<0.05). Females demonstrated similar (6 & 12 months) or better (12 months) cognition, despite greater pathology across timepoints. Correlations implicated microglial recruitment in EH-related effects, supported by morphological analysis of prefrontal regions (p<0.05).
Conclusion
Our findings highlight the critical role of early postnatal experiences and sex in shaping resilience in the context of AD pathology.