Impact of the Cellular Prion Protein on Amyloid-β and 3PO-Tau Processing

Abstract

Previous studies indicate an important role for the cellular prion protein (PrP^C) in the development of Alzheimer's disease (AD) pathology. In the present study, we analyzed the involvement of PrP^C in different pathological mechanisms underlying AD: the processing of the amyloid-β protein precursor (AβPP) and its interaction with AβPP, tau, and different phosphorylated forms of the tau protein (p-tau). The effect of PrP^C on tau expression was investigated in various cellular compartments using a HEK293 cell model expressing a tau mutant (3PO-tau) or wild type (WT)-tau.

We could show that PrP^C reduces AβPP cleavage, leading to decreased levels of Aβ₄₀ and sAβPP without changing the protein expression of AβPP, β-secretase, or γ-secretase. Tau and its phosphorylated forms were identified as interactions partners for PrP^C, raising the question as to whether PrP^C might also be involved in tau pathology. Overexpression of PrP^C in PRNP and 3PO-tau transfected cells resulted in a reduction of 3PO-tau and p-tau as well as a decrease of 3PO-tau-related toxicity. In addition, we used the transgenic PrP^C knockout (Prnp0/0) mouse line to study the dynamics of tau phosphorylation, an important pathological hallmark in the pathogenesis of AD in vivo. There, an effect of PrP^C on tau expression could be observed under oxidative stress conditions but not during aging. In summary, we provide further evidence for interactions of PrP^C with proteins that are known to be the key players in AD pathogenesis. We identified tau and its phosphorylated forms as potential PrP-interactors and report a novel protective function of PrP^C in AD-like tau pathology.