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

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.
(© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)