p35 Hemizygous Deletion in 5xFAD Mice Increases Aβ Plaque Load in Males but Not in Females

Abstract

Increased amyloid beta (Aβ) deposition is implicated in early stages of Alzheimer's disease (AD). Although aberrant Cdk5 activity mediated by Cdk5/p25 is suggested to promote Aβ plaque deposition, the effects of Cdk5 inhibition on Aβ plaque loads in AD mouse models have been equivocal, possibly due to the fact that Cdk5 can be activated by p35 or p39 and their cleaved products. Here we evaluated the effect of p35 knockdown on Aβ plaque formation by constitutively knocking out a single p35 allele in 5xFAD mice. Surprisingly, our results show that the simultaneous reduction in the levels of p35 and p25 increases cortical Aβ plaque loads in male 5xFAD mice, but not in females. This change is associated with male specific decrease in pSer9 GSK3β levels. Furthermore, p35 hemizygous deletion has sexually dimorphic effects on Iba1 and GFAP protein levels. Our findings demonstrate sex differences in the effects of p35 reduction on biochemical pathways relevant to the modulation of Aβ plaque deposition and confirm the importance of examining both sexes in preclinical AD research.

Keywords: 5xFAD mice; Alzheimer's disease; Cdk5; Sex differences; amyloidogenesis; p35.