Reduced brain volumes in mice expressing APP-Austrian mutation but not in mice expressing APP-Swedish–Austrian mutations

Abstract

We previously described two transgenic mouse lines expressing sub-endogenous levels of the ‘Austrian’ APP-T714I mutation (driven by the prenatally active PDGF-β promoter; APP-Au mice) and showing intraneuronal Aβ pathology and reduced brain volumes on MRI at 12 and 20 months of age. To further investigate whether reduced brain sizes were caused by neurodegeneration or a neurodevelopmental defect, we now measured brain volumes as early as postnatal day 10. At this age, a distinguishable reduction in brain volumes was absent, indicating that brain volume deficits in APP-Au mice are not caused by a neurodevelopmental defect. To further study the association between intraneuronal Aβ and reduced brain volumes, we further generated and analyzed an APP transgenic mouse model expressing both Austrian and Swedish (K670N/M671L) mutations (APP-SwAu mice). APP-Swedish mutation is known to lead to altered APP processing in the secretory pathway, precluding its later processing in endosomal–lysosomal compartments, the site of intraneuronal Aβ accumulation. Also, to have higher levels of transgene expression only after birth, a murine Thy-1 promoter was utilized for APP-SwAu mouse lines. Despite having five times higher transgene APP levels compared to APP-Au mice, APP-SwAu mice showed significantly lower intraneuronal Aβ levels in the absence of reduced brain volumes, suggesting that intraneuronal Aβ accumulation is related to reduced brain volumes in APP-Au mice. These data also provide a first in vivo indication of altered processing of APP-Swedish at sub-endogenous levels, an effect not observed in mouse models expressing the APP-Swedish mutation in high amounts.