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PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases

Nature Medicine volume 19, pages 1124–1131 (2013)Cite this article

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Abstract

α-secretase–mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrPC) prevents its conversion into misfolded, pathogenic prions (PrPSc). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α–converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrPSc or isolated from APP-transgenic mice with amyloid pathology. 3-phosphoinositide–dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1–mediated internalization of TACE. This dysregulation of TACE increases PrPSc and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrPC and TNFR1, and attenuates PrPSc- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrPSc infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.

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Figure 1: Prion infection reduces TNFR1 shedding and increases cellular sensitivity to sTNF-α toxicity.
Figure 2: Activation of PDK1 in prion-infected cells promotes TACE phosphorylation and internalization.
Figure 3: PDK1 inhibition increases TACE-mediated cleavage of TNFR1 and α-secretase processing of PrPC in prion-infected neurons.
Figure 4: PDK1 inhibition attenuates prion disease in mice.
Figure 5: Increased PDK1 activity in hippocampal neurons from mice with Alzheimer's disease–like pathology impairs TACE activity.
Figure 6: PDK1 inhibition reduces Alzheimer's disease–like pathology and cognitive and memory impairments in Tg2576 mice.

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Acknowledgements

We thank G. Bombarde, V. Mutel, F. d'Agostini, G. Zürcher, E. Borroni, J.G. Richards, Z. Lam, M. Bühler, N. Pierron and R. Hochköppler for skillful methodological assistance, C. Vidal for stereotaxic injection of prion strains in mice cerebella, H. Laude and V. Beringue for the use of P3 facilities and F. Brouillard for two-dimensional gel electrophoresis advice. We acknowledge S. Blanquet, M. Briley and A. Baudry for helpful discussions and critical reading of the manuscript. This work was supported by the French Agence Nationale pour la Recherche (Prions&SensiTNF, 1312 01) and INSERM. M.P. is a postdoctoral fellow of French Agence Nationale pour la Recherche. A.A.B. is funded by Domaine d'Intérêt Majeur - Maladies Infectieuses - Région Ile-de-France.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale (INSERM), UMR-S 747, Paris, France

    Mathéa Pietri, Caroline Dakowski, Aurélie Alleaume-Butaux, Julia Hernandez-Rapp, Sophie Mouillet-Richard, Odile Kellermann & Benoit Schneider

  2. Université Paris Descartes, Sorbonne Paris Cité, UMR-S 747, Paris, France

    Mathéa Pietri, Caroline Dakowski, Aurélie Alleaume-Butaux, Julia Hernandez-Rapp, Sophie Mouillet-Richard, Odile Kellermann & Benoit Schneider

  3. Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S 975, Equipe “Alzheimer's and Prion diseases, Paris, France

    Samia Hannaoui & Stéphane Haik

  4. INSERM, UMR-S 975, Paris, France

    Samia Hannaoui & Stéphane Haik

  5. Centre National de la Recherche Scientifique (CNRS) UMR 7225, Paris, France

    Samia Hannaoui & Stéphane Haik

  6. Université Paris Sud 11, ED419 Biosigne, Orsay, France

    Julia Hernandez-Rapp

  7. Cytologie et Cytopathologie Neuronales, Institut des Neurosciences Cellulaires & Intégratives, CNRS UPR 3212, Strasbourg, France

    Audrey Ragagnin & Yannick Bailly

  8. Neurobiologie des Processus Adaptatifs, CNRS UMR 7102, Université Pierre et Marie Curie–Paris 6, Paris, France

    Jean-Michel Peyrin

  9. Assistance Publique–Hôpitaux de Paris, Service de Biochimie, INSERM UMR-S 942, Hôpital Lariboisière, Paris, France

    Jean-Marie Launay

  10. Pharma Research Department, Hoffmann La Roche, Basel, Switzerland

    Jean-Marie Launay

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  1. Mathéa Pietri
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Contributions

M.P., J.-M.L., O.K. and B.S. conceptualized the study. M.P., C.D., Y.B., J.-M.P., S.H., A.A.-B., J.H.-R., A.R., S.M.-R., S.H. and B.S. performed experiments, and all authors participated in designing experiments and in analyzing and interpreting data. M.P., O.K. and B.S. wrote the manuscript. J.M.L. and B.S. supervised the project.

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Correspondence to Jean-Marie Launay or Benoit Schneider.

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Pietri, M., Dakowski, C., Hannaoui, S. et al. PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases. Nat Med 19, 1124–1131 (2013). https://doi.org/10.1038/nm.3302

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