Production of seedable Amyloid-\u03b2 peptides in model of prion diseases upon PrPSc-induced PDK1 overactivation

Juliette Ezpeleta,Yannick Bailly,Vincent Baudouin,Anne-Marie Haeberlé,Jean-Marie Launay,Anne Baudry,François Boudet-Devaud,Odile Kellermann,Mathéa Pietri,Benoit Schneider,Zaira E Arellano-Anaya

doi:10.1038/s41467-019-11333-3

Abstract

The presence of amyloid beta (Aβ) plaques in the brain of some individuals with Creutzfeldt-Jakob or Gertsmann-Straussler-Scheinker diseases suggests that pathogenic prions (PrPSc) would have stimulated the production and deposition of Aβ peptides. We here show in prion-infected neurons and mice that deregulation of the PDK1-TACE α-secretase pathway reduces the Amyloid Precursor Protein (APP) α-cleavage in favor of APP β-processing, leading to Aβ40/42 accumulation. Aβ predominates as monomers, but is also found as trimers and tetramers. Prion-induced Aβ peptides do not affect prion replication and infectivity, but display seedable properties as they can deposit in the mouse brain only when seeds of Aβ trimers are co-transmitted with PrPSc. Importantly, brain Aβ deposition accelerates death of prion-infected mice. Our data stress that PrPSc, through deregulation of the PDK1-TACE-APP pathway, provokes the accumulation of Aβ, a prerequisite for the onset of an Aβ seeds-induced Aβ pathology within a prion-infectious context.

Highlights

The presence of amyloid beta (Aβ) plaques in the brain of some individuals with CreutzfeldtJakob or Gertsmann-Straussler-Scheinker diseases suggests that pathogenic prions (PrPSc) would have stimulated the production and deposition of Aβ peptides
1C11-derived serotonergic neuronal cells chronically infected by the Fukuoka-1 prion strain (Fk-1C115-HT cells) (Fig. 1a–b). We assessed whether this rise of Aβ in the culture medium of Fk-1C115-HT cells would relate to a phosphoinositide-dependent kinase 1 (PDK1) overactivity, downstream TACE internalization[23] and subsequent reduction of Amyloid Precursor Protein (APP) α-cleavage
The rescue of APP α-processing in prioninfected neuronal cells upon PDK1 inhibition depended on the restoration of TACE activity, since TACE inhibition with TAPI-2 (100 μM, 1 h) abrogated the decrease of Aβ40/42 and sAPPβ and the reciprocal increase of sAPPα induced by BX912 (Fig. 1a–d)

Summary

Introduction

The presence of amyloid beta (Aβ) plaques in the brain of some individuals with CreutzfeldtJakob or Gertsmann-Straussler-Scheinker diseases suggests that pathogenic prions (PrPSc) would have stimulated the production and deposition of Aβ peptides. The capacity of synthetic Aβ trimers to promote Aβ deposition independently from prion infection was challenged in APP23 mice injected with homogenates of 2.5 × 105 uninfected 1C11 cells supplemented with human Aβ trimers.

Results

Conclusion