Previous studies indicate an important role for the cellular prion protein (PrPC) in the development of Alzheimer's disease (AD) pathology. In the present study, we analyzed the involvement of PrPC 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 PrPC 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 PrPC 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 PrPC, raising the question as to whether PrPC might also be involved in tau pathology. Overexpression of PrPC 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 PrPC 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 PrPC on tau expression could be observed under oxidative stress conditions but not during aging. In summary, we provide further evidence for interactions of PrPC 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 PrPC in AD-like tau pathology.