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

Juliette Ezpeleta, Vincent Baudouin, Zaira E. Arellano-Anaya, François Boudet-Devaud, Mathéa Pietri, Anne Baudry, Anne-Marie Haeberlé, Yannick Bailly, Odile Kellermann, Jean-Marie Launay () and Benoit Schneider ()
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Juliette Ezpeleta: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
Vincent Baudouin: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
Zaira E. Arellano-Anaya: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
François Boudet-Devaud: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
Mathéa Pietri: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
Anne Baudry: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
Anne-Marie Haeberlé: Trafic Membranaire dans les Cellules du Système Nerveux, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212
Yannick Bailly: Trafic Membranaire dans les Cellules du Système Nerveux, Institut des Neurosciences Cellulaires et Intégratives, CNRS UPR 3212
Odile Kellermann: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124
Jean-Marie Launay: Assistance Publique des Hôpitaux de Paris, INSERM UMR 942, Hôpital Lariboisière
Benoit Schneider: Université Paris Descartes, Sorbonne Paris Cité, UFR des Sciences Fondamentales et Biomédicales, UMR 1124

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11333-3

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