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Nat Commun. 2019 Aug 1;10(1):3442. doi: 10.1038/s41467-019-11333-3.

Production of seedable Amyloid-β peptides in model of prion diseases upon PrPSc-induced PDK1 overactivation.

Author information

1
Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124, 75006, Paris, France.
2
INSERM, UMR 1124, 75006, Paris, France.
3
Trafic Membranaire dans les Cellules du Système Nerveux, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212, 67000, Strasbourg, France.
4
Assistance Publique des Hôpitaux de Paris, INSERM UMR 942, Hôpital Lariboisière, 75010, Paris, France. jean-marie.launay@inserm.fr.
5
Pharma Research Department, Hoffmann La Roche Ltd, 4070, Basel, Switzerland. jean-marie.launay@inserm.fr.
6
Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124, 75006, Paris, France. benoit.schneider@parisdescartes.fr.
7
INSERM, UMR 1124, 75006, Paris, France. benoit.schneider@parisdescartes.fr.

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.

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