Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Aguzzi, A., Baumann, F. & Bremer, J. The prion's elusive reason for being. Annu. Rev. Neurosci. 31, 439–477 (2008).

    Article  CAS  PubMed  Google Scholar 

  2. Zhang, H., Ma, Q., Zhang, Y.W. & Xu, H. Proteolytic processing of Alzheimer's β-amyloid precursor protein. J. Neurochem. 120 (suppl. 1), 9–21 (2012).

    Article  CAS  PubMed  Google Scholar 

  3. De Strooper, B., Vassar, R. & Golde, T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat. Rev. Neurol. 6, 99–107 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Barger, S.W. & Harmon, A.D. Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388, 878–881 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Meziane, H. et al. Memory-enhancing effects of secreted forms of the β-amyloid precursor protein in normal and amnestic mice. Proc. Natl. Acad. Sci. USA 95, 12683–12688 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Westergard, L., Turnbaugh, J.A. & Harris, D.A. A naturally occurring, C-terminal fragment of the prion protein delays disease and acts as a dominant negative inhibitor of PrPSc formation. J. Biol. Chem. 286, 44234–44242 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Edwards, D.R., Handsley, M.M. & Pennington, C.J. The ADAM metalloproteinases. Mol. Aspects Med. 29, 258–289 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gooz, M. ADAM-17: the enzyme that does it all. Crit. Rev. Biochem. Mol. Biol. 45, 146–169 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vincent, B. et al. The disintegrins ADAM10 and TACE contribute to the constitutive and phorbol ester-regulated normal cleavage of the cellular prion protein. J. Biol. Chem. 276, 37743–37746 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Buxbaum, J.D. et al. Evidence that tumor necrosis factor α converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor. J. Biol. Chem. 273, 27765–27767 (1998).

    Article  CAS  PubMed  Google Scholar 

  11. Sennvik, K. et al. Levels of α- and β-secretase cleaved amyloid precursor protein in the cerebrospinal fluid of Alzheimer's disease patients. Neurosci. Lett. 278, 169–172 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Yadavalli, R. et al. Calpain-dependent endoproteolytic cleavage of PrPSc modulates scrapie prion propagation. J. Biol. Chem. 279, 21948–21956 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Adrain, C., Zettl, M., Christova, Y., Taylor, N. & Freeman, M. Tumor necrosis factor signaling requires iRhom2 to promote trafficking and activation of TACE. Science 335, 225–228 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. D'Alessio, A. et al. Plasma membrane microdomains regulate TACE-dependent TNFR1 shedding in human endothelial cells. J. Cell Mol. Med. 16, 627–636 (2012).

    PubMed  Google Scholar 

  15. Wang, Y., Herrera, A.H., Li, Y., Belani, K.K. & Walcheck, B. Regulation of mature ADAM17 by redox agents for L-selectin shedding. J. Immunol. 182, 2449–2457 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Pradines, E. et al. Cellular prion protein coupling to TACE-dependent TNF-α shedding controls neurotransmitter catabolism in neuronal cells. J. Neurochem. 110, 912–923 (2009).

    Article  CAS  PubMed  Google Scholar 

  17. Mouillet-Richard, S. et al. Regulation by neurotransmitter receptors of serotonergic or catecholaminergic neuronal cell differentiation. J. Biol. Chem. 275, 9186–9192 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Mouillet-Richard, S. et al. Prions impair bioaminergic functions through serotonin- or catecholamine-derived neurotoxins in neuronal cells. J. Biol. Chem. 283, 23782–23790 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cronier, S., Beringue, V., Bellon, A., Peyrin, J.M. & Laude, H. Prion strain- and species-dependent effects of antiprion molecules in primary neuronal cultures. J. Virol. 81, 13794–13800 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. MacEwan, D.J. TNF receptor subtype signalling: differences and cellular consequences. Cell Signal. 14, 477–492 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Mouillet-Richard, S. et al. Signal transduction through prion protein. Science 289, 1925–1928 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, Q. et al. Phosphorylation of TNF-α converting enzyme by gastrin-releasing peptide induces amphiregulin release and EGF receptor activation. Proc. Natl. Acad. Sci. USA 103, 6901–6906 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Pradines, E. et al. Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-β clearance. Cell Death Dis. 4, e456 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kloo, B. et al. Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell-like diffuse large B-cell lymphoma cells. Proc. Natl. Acad. Sci. USA 108, 272–277 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Allinson, T.M., Parkin, E.T., Turner, A.J. & Hooper, N.M. ADAMs family members as amyloid precursor protein α-secretases. J. Neurosci. Res. 74, 342–352 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Laurén, J., Gimbel, D.A., Nygaard, H.B., Gilbert, J.W. & Strittmatter, S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-β oligomers. Nature 457, 1128–1132 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Benilova, I. & De Strooper, B. Prion protein in Alzheimer's pathogenesis: a hot and controversial issue. EMBO Mol. Med. 2, 289–290 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Kawarabayashi, T. et al. Age-dependent changes in brain, CSF, and plasma amyloid β protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J. Neurosci. 21, 372–381 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Manook, A. et al. Small-animal PET imaging of amyloid-β plaques with [11C]PiB and its multi-modal validation in an APP/PS1 mouse model of Alzheimer's disease. PLoS ONE 7, e31310 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wesson, D.W. & Wilson, D.A. Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein (APP) mice. Behav. Brain Res. 216, 408–413 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Oddo, S. et al. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39, 409–421 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Oakley, H. et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26, 10129–10140 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Santuccione, A., Sytnyk, V., Leshchyns'ka, I. & Schachner, M. Prion protein recruits its neuronal receptor NCAM to lipid rafts to activate p59fyn and to enhance neurite outgrowth. J. Cell Biol. 169, 341–354 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Winklhofer, K.F., Tatzelt, J. & Haass, C. The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases. EMBO J. 27, 336–349 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pietri, M. et al. Overstimulation of PrPC signaling pathways by prion peptide 106–126 causes oxidative injury of bioaminergic neuronal cells. J. Biol. Chem. 281, 28470–28479 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Nixon, R.R. Prion-associated increases in Src-family kinases. J. Biol. Chem. 280, 2455–2462 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Um, J.W. et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15, 1227–1235 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Larson, M. et al. The complex PrPc-Fyn couples human oligomeric Aβ with pathological tau changes in Alzheimer's disease. J. Neurosci. 32, 16857–16871 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mallucci, G. et al. Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis. Science 302, 871–874 (2003).

    Article  CAS  PubMed  Google Scholar 

  41. Li, R. et al. Tumor necrosis factor death receptor signaling cascade is required for amyloid-β protein–induced neuron death. J. Neurosci. 24, 1760–1771 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. He, P. et al. Deletion of tumor necrosis factor death receptor inhibits amyloid β generation and prevents learning and memory deficits in Alzheimer's mice. J. Cell Biol. 178, 829–841 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Williams, A., Van Dam, A.M., Ritchie, D., Eikelenboom, P. & Fraser, H. Immunocytochemical appearance of cytokines, prostaglandin E2 and lipocortin-1 in the CNS during the incubation period of murine scrapie correlates with progressive PrP accumulations. Brain Res. 754, 171–180 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Mehlhorn, G., Hollborn, M. & Schliebs, R. Induction of cytokines in glial cells surrounding cortical β-amyloid plaques in transgenic Tg2576 mice with Alzheimer pathology. Int. J. Dev. Neurosci. 18, 423–431 (2000).

    Article  CAS  PubMed  Google Scholar 

  45. Perry, V.H. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav. Immun. 18, 407–413 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Holmes, C. et al. Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768–774 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Singh, T. & Newman, A.B. Inflammatory markers in population studies of aging. Ageing Res. Rev. 10, 319–329 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. McKhann, G. et al. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34, 939–944 (1984).

    Article  CAS  PubMed  Google Scholar 

  49. Vidal, C. et al. Early dnmysfunction of central 5-HT system in a murine model of bovine spongiform encephalopathy. Neuroscience 160, 731–743 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Baudry, A., Mouillet-Richard, S., Schneider, B., Launay, J.M. & Kellermann, O. miR-16 targets the serotonin transporter: a new facet for adaptive responses to antidepressants. Science 329, 1537–1541 (2010).

    Article  CAS  PubMed  Google Scholar 

  51. Kempster, S., Bate, C. & Williams, A. Simvastatin treatment prolongs the survival of scrapie-infected mice. Neuroreport 18, 479–482 (2007).

    Article  CAS  PubMed  Google Scholar 

  52. Cramer, P.E. et al. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Brewer, G.J. & Torricelli, J.R. Isolation and culture of adult neurons and neurospheres. Nat. Protoc. 2, 1490–1498 (2007).

    Article  CAS  PubMed  Google Scholar 

  54. Loubet, D. et al. Neuritogenesis: the prion protein controls β1 integrin signaling activity. Faseb J. 26, 678–690 (2012).

    Article  CAS  PubMed  Google Scholar 

  55. McCabe, A., Dolled-Filhart, M., Camp, R.L. & Rimm, D.L. Automated quantitative analysis (AQUA) of in situ protein expression, antibody concentration, and prognosis. J. Natl. Cancer Inst. 97, 1808–1815 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Mouillet-Richard, S., Laurendeau, I., Vidaud, M., Kellermann, O. & Laplanche, J.L. Prion protein and neuronal differentiation: quantitative analysis of prnp gene expression in a murine inducible neuroectodermal progenitor. Microbes Infect. 1, 969–976 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Bailly, Y. et al. Prion protein (PrPc) immunocytochemistry and expression of the green fluorescent protein reporter gene under control of the bovine PrP gene promoter in the mouse brain. J. Comp. Neurol. 473, 244–269 (2004).

    Article  CAS  PubMed  Google Scholar 

  58. Heitz, S. et al. BAX contributes to Doppel-induced apoptosis of prion-protein–deficient Purkinje cells. Dev. Neurobiol. 67, 670–686 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Song, K.S. et al. Co-purification and direct interaction of Ras with caveolin, an integral membrane protein of caveolae microdomains. Detergent-free purification of caveolae microdomains. J. Biol. Chem. 271, 9690–9697 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Soond, S.M., Everson, B., Riches, D.W.H. & Murphy, G. ERK-mediated phosphorylation of Thr735 in TNF-α–converting enzyme and its potential role in TACE protein trafficking. J. Cell Sci. 118, 2371–2380 (2005).

    Article  CAS  PubMed  Google Scholar 

  61. Slot, J.W., Geuze, H.J., Gigengack, S., Lienhard, G.E. & James, D.E. Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. J. Cell Biol. 113, 123–135 (1991).

    Article  CAS  PubMed  Google Scholar 

  62. Slot, J.W. & Geuze, H.J. A new method of preparing gold probes for multiple-labeling cytochemistry. Eur. J. Cell Biol. 38, 87–93 (1985).

    CAS  PubMed  Google Scholar 

  63. Hofler, A. et al. Study of the PDK1/AKT signaling pathway using selective PDK1 inhibitors, HCS, and enhanced biochemical assays. Anal. Biochem. 414, 179–186 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Bate, C., Langeveld, J. & Williams, A. Manipulation of PrPres production in scrapie-infected neuroblastoma cells. J. Neurosci. Methods 138, 217–223 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Raucci, F. et al. Proliferative activity in the frog brain: a PCNA-immunohistochemistry analysis. J. Chem. Neuroanat. 32, 127–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  66. Moss, T.J., Rosenblatt, H.M. & Seeger, R.C. Expression of a developmental stage-specific antigen by neuronal precursor cells of human fetal cerebellum. J. Neuroimmunol. 20, 3–14 (1988).

    Article  CAS  PubMed  Google Scholar 

  67. Schieb, H. et al. β-amyloid peptide variants in brains and cerebrospinal fluid from amyloid precursor protein (APP) transgenic mice: comparison with human Alzheimer amyloid. J. Biol. Chem. 286, 33747–33758 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Ciccimaro, E. & Blair, I.A. Stable-isotope dilution LC-MS for quantitative biomarker analysis. Bioanalysis 2, 311–341 (2010).

    Article  CAS  PubMed  Google Scholar 

Download references

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.

Author information

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

Authors
  1. Mathéa Pietri
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline Dakowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samia Hannaoui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aurélie Alleaume-Butaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julia Hernandez-Rapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Audrey Ragagnin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sophie Mouillet-Richard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Stéphane Haik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yannick Bailly
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jean-Michel Peyrin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean-Marie Launay
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Odile Kellermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Benoit Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Jean-Marie Launay or Benoit Schneider.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–12 and Supplementary Tables 1 and 2 (PDF 6384 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.3302

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research