Cellular prion protein acts as mediator of amyloid beta uptake by caveolin‐1 causing cellular dysfunctions in vitro and in vivo

Abstract

Abstract INTRODUCTION Cellular prion protein (PrP C ) was implicated in amyloid beta (Aβ)‐induced toxicity in Alzheimer's disease (AD), but the precise molecular mechanisms involved in this process are unclear. METHODS Double transgenic mice were generated by crossing Prnp knockout (KO) with 5xFAD mice, and light‐sheet microscopy was used for whole brain tissue analyses. PrP C ‐overexpressing cells were developed for in vitro studies, and microscopy was used to assess co‐localization of proteins of interest. Surface‐plasmon resonance (SPR) was used to investigate protein‐binding characteristics. RESULTS In vivo, PrP C levels correlated with reduced lifespan and cognitive and motor function, and its ablation disconnected behavior deficits from Aβ levels. Light‐sheet microscopy showed that PrP C influenced Aβ‐plaque burden but not the distribution of those plaques. Interestingly, caveolin‐1 (Cav‐1) KO neurons significantly reduced intracellular Aβ‐oligomer (Aβo) uptake when compared to wild‐type neurons. DISCUSSION The findings shed new light on the relevance of intracellular Aβo, suggesting that PrP C and Cav‐1 modulate intracellular Aβ levels and the Aβ‐plaque load. Highlights PrP C expression adversely affects lifespan and behavior in 5xFAD mice. PrP C increases Aβ1‐40 and Aβ1‐42 levels and Aβ‐plaque load in 5xFAD mice. Cav‐1 interacts with both PrP C and Aβ peptides. Knocking out Cav‐1 leads to a significant reduction in intracellular Aβ levels.