The effect of prion protein expression on amyloid‐beta pathology

Abstract

AbstractBackgroundWe have developed multiple knock‐in mouse models that express humanised Aβ (AppNL‐F) with varying levels of PrPC expression (AppNL‐F, AppNL‐F_Tg20, AppNL‐F_PrPKO, AppNL‐F_hTauKI and AppNL‐F_hTauKI_PrPKO) to investigate the role of PrPC in knock‐in mice before and after inoculation with human AD brain homogenates.MethodUninoculated knock‐in mice with varying levels of PrPC were characterised using biochemical and histological techniques. We went on to characterise AppNL‐F, AppNL‐F_Tg20, AppNL‐F_PrPKO, AppNL‐F_hTauKI and AppNL‐F_hTauKI_PrPKO mice after inoculation with human brain homogenates.ResultAn age‐dependent increase in Aβ42 levels in all animals at 10 months old was observed compared to their 6 month old counterparts. We saw an accumulation of activated astrocytes around the Aβ plaques with higher levels of astrogliosis seen in the AppNL‐F_Tg20 animals at all ages compared to AppNL‐F, AppNL‐F_PrPKO, AppNL‐F_hTauKI and AppNL‐F_hTauKI_PrPKO mice. Synaptic protein fractions extracted from AppNL‐F_Tg20 mice inoculated human AD brain homogenate showed a significant increase in Fyn and Pyk2 protein phosphorylation when compared to vehicle and control human brain homogenate inoculated AppNL‐F_Tg20 mice. This effect was statistically significant for both proteins at 8 months post‐inoculation (mpi) and was further exacerbated at 12 mpi. The results at 8 and 12mpi were independent of guanidine hydrochloride‐soluble Aβ42 levels and Aβ plaque coverage in the mouse brains. We went on to find significant differences in tau hyperphosphorylation and Aβ plaque coverage between inoculated AppNL‐F_hTauKI and AppNL‐F_hTauKI_PrPKO mice which was independent of guanidine hydrochloride‐soluble Aβ42 levels.ConclusionThe level of PrPC expression in two knock‐in mouse models inoculated with human brain homogenate was shown to have an effect on synaptic protein phosphorylation at 8 and 12mpi. This was independent of Aβ42 levels and Aβ plaque coverage in the mouse brains.