title: 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.
authors.affiliation: Department of Neurology, Clinical Dementia Center and University Medical Center Göttingen, Göttingen, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Schmitz
authors.forename: Katharina
authors.initials: K
authors.lastname: Wulf
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Signore
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Schulz-Schaeffer
authors.forename: Pawel
authors.initials: P
authors.lastname: Kermer
authors.forename: Mathias
authors.initials: M
authors.lastname: Bähr
authors.forename: Fred S
authors.initials: FS
authors.lastname: Wouters
authors.forename: Saima
authors.initials: S
authors.lastname: Zafar
authors.forename: Inga
authors.initials: I
authors.lastname: Zerr
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D011328:Prions / Q000378:metabolism*; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011328:Prions; D016875:tau Proteins; D053829:Amyloid Precursor Protein Secretases
keywords: 3PO-tau; Alzheimer's disease; amyloid; cellular prion protein; neuroprotection; p-tau; β-secretase