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

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- protein precursor (APP) and its interaction with APP, 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 APP cleavage, leading to decreased levels of A40 and sAPP without changing the protein expression of APP, -secretase, or -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.