Sex differences in behaviour and molecular pathology in the 5XFAD model

Annesha Sil, Arina Erfani, Nicola Lamb, Rachel Copland, Bettina Platt* (Corresponding Author), Gernot Riedel

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Background
The prevalence of Alzheimer’s Disease (AD) is greater in women compared to men, but the reasons for this remain unknown. This sex difference has been widely neglected in experimental studies using transgenic mouse models of AD.
Objective
Here, we studied behaviour and molecular pathology of 5-month-old 5XFAD mice, which express mutated human amyloid precursor protein and presenilin-1 on a C57BL/6J background, vs. their wildtype littermate controls, to compared both sex- and genotype-dependent differences.
Methods
A novel behavioural paradigm was utilised (OF-NO-SI), comprising activity measures (Open Field, OF) arena, followed by Novel Object exploration (NO) and Social Interaction (SI) of a sex-matched conspecific. Each segment consisted of two repeated trials to assess between-trial habituation. Subsequently, brain pathology (amyloid load, stress response and inflammation markers, synaptic integrity, trophic support) was assessed using qPCR and Western blotting.
Results
Female 5XFAD mice had higher levels of human APP and beta-amyloid (Aβ) and heightened inflammation vs males. These markers correlated with hyperactivity observed in both sexes, yet only female 5XFAD mice presented with deficits in object and social exploration. Male animals had higher expression of stress markers and neurotrophic factors irrespective of genotype, this correlated with
cognitive performance.
Conclusion
The impact of sex on AD-relevant phenotypes is in line with human data and emphasises the necessity of appropriate study design and reporting. Differential molecular profiles observed in male vs. female mice offer insights into possible protective mechanisms, and hence treatment strategies.
Original languageEnglish
JournalJournal of Alzheimer's Disease
Publication statusAccepted/In press - 22 Oct 2021

Keywords

  • beta-amyloid
  • cognition
  • activity
  • social
  • male
  • female
  • ER STRESS
  • inflammation
  • trophic factors

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