Effects of BACE1 haploinsufficiency on APP processing and Aβ concentrations in male and female 5XFAD Alzheimer mice at different disease stages.

β-Site APP-cleaving enzyme 1 (BACE1) initiates the generation of amyloid-β (Aβ), thus representing a prime therapeutic target for Alzheimer's disease (AD). Previous work including ours has used BACE1 haploinsufficiency (BACE1(+/-); i.e., 50% reduction) as a therapeutic relevant model to evaluate the efficacy of partial β-secretase inhibition. However, it is unclear whether the extent of Aβ reductions in amyloid precursor protein (APP) transgenic mice with BACE1(+/-) gene ablation may vary with sex or disease progression. Here, we compared the impacts of BACE1 haploinsufficiency on Aβ concentrations and APP processing in 5XFAD Alzheimer mice (1) between males and females and (2) between different stages with moderate and robust Aβ accumulation. First, male and female 5XFAD mice at 6-7 months of age showed equivalent levels of Aβ, BACE1, full-length APP and its metabolites. BACE1 haploinsufficiency significantly lowered soluble Aβ oligomers, total Aβ42 levels and plaque burden in 5XFAD mouse brains irrespective of sex. Furthermore, there was no sex difference in reductions of β-cleavage products of APP (C99 and sAPPβ) found in BACE1(+/-)·5XFAD mice relative to BACE1(+/+)·5XFAD controls. Meanwhile, APP and sAPPα levels in BACE1(+/-)·5XFAD mice were higher than those of 5XFAD controls regardless of sex. Based on these observations, we next combined male and female data to examine the effects of BACE1 haploinsufficiency in 5XFAD mice at 12-14 months of age, as compared with those in 6-7-month-old 5XFAD mice. Oligomeric Aβ and C99 levels were dramatically elevated in older 5XFAD mice. Although the β-metabolites of APP were significantly reduced by BACE1 haploinsufficiency in both age groups, high levels of these toxic amyloidogenic fragments remained in 12-14-month-old BACE1(+/-)·5XFAD mice. The present findings are consistent with our previous behavioral data showing that BACE1 haploinsufficiency rescues memory deficits in 5XFAD mice irrespective of sex but only in the younger age group.