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Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β

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Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer’s disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer’s disease. Despite the importance of plaques to Alzheimer’s disease, oligomers are considered to be the principal toxic forms of amyloid-β1,2. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity3, microtubule loss4, impaired memory and learning5, and neuritic degeneration6, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β7,8 are strongly associated with Alzheimer’s disease, are more toxic than amyloid-β, residues 1–42 (Aβ1–42) and Aβ1–40, and have been proposed as initiators of Alzheimer’s disease pathogenesis9,10. Here we report a mechanism by which pE-Aβ may trigger Alzheimer’s disease. Aβ3(pE)–42 co-oligomerizes with excess Aβ1–42 to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ1–42 alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ3(pE)–42 plus 95% Aβ1–42 (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ1–42 monomers in the absence of additional Aβ3(pE)–42. LNOs isolated from human Alzheimer’s disease brain contained Aβ3(pE)–42, and enhanced Aβ3(pE)–42 formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ3(pE)–42 confers tau-dependent neuronal death and causes template-induced misfolding of Aβ1–42 into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ3(pE)–42 acts similarly at a primary step in Alzheimer’s disease pathogenesis.

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Figure 1: Tau-dependent cytotoxicity of oligomers formed by co-incubation of Aβ3(pE)–42 and Aβ1–42.
Figure 2: 3(pE)–42 and Aβ 1–42 form metastable, cytotoxic, hybrid oligomers.
Figure 3: The cytotoxic species are low- n , prion-like oligomers.
Figure 4: 3(pE)–42 in vivo.

Change history

  • 30 May 2012

    Further grant information was added to Acknowledgements.


  1. 1

    Gandy, S. et al. Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-β oligomers. Ann. Neurol. 68, 220–230 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Walsh, D. M. & Selkoe, D. J. Aβ oligomers—a decade of discovery. J. Neurochem. 101, 1172–1184 (2007)

    CAS  Article  Google Scholar 

  3. 3

    Rapoport, M., Dawson, H. N., Binder, L. I., Vitek, M. P. & Ferreira, A. Tau is essential to β-amyloid-induced neurotoxicity. Proc. Natl Acad. Sci. USA 99, 6364–6369 (2002)

    ADS  CAS  Article  Google Scholar 

  4. 4

    King, M. E. et al. Tau-dependent microtubule disassembly initiated by pre-fibrillar β-amyloid. J. Cell Biol. 175, 541–546 (2006)

    MathSciNet  CAS  Article  Google Scholar 

  5. 5

    Roberson, E. D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer’s disease mouse model. Science 316, 750–754 (2007)

    ADS  CAS  Article  Google Scholar 

  6. 6

    Jin, M. et al. Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc. Natl Acad. Sci. USA 108, 5819–5824 (2011)

    ADS  CAS  Article  Google Scholar 

  7. 7

    Mori, H., Takio, K., Ogawara, M. & Selkoe, D. J. Mass spectrometry of purified amyloid β protein in Alzheimer’s disease. J. Biol. Chem. 267, 17082–17086 (1992)

    CAS  PubMed  Google Scholar 

  8. 8

    Saido, T. C. et al. Dominant and differential deposition of distinct β-amyloid peptide species, AβN3(pE), in senile plaques. Neuron 14, 457–466 (1995)

    CAS  Article  Google Scholar 

  9. 9

    Jawhar, S., Wirths, O. & Bayer, T. A. Pyroglutamate amyloid-β (Aβ): a hatchet man in Alzheimer disease. J. Biol. Chem. 286, 38825–38832 (2011)

    CAS  Article  Google Scholar 

  10. 10

    Schilling, S. et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Aβ and Alzheimer’s disease-like pathology. Nature Med. 14, 1106–1111 (2008)

    CAS  Article  Google Scholar 

  11. 11

    Tabaton, M. et al. Soluble amyloid β-protein is a marker of Alzheimer amyloid in brain but not in cerebrospinal fluid. Biochem. Biophys. Res. Commun. 200, 1598–1603 (1994)

    CAS  Article  Google Scholar 

  12. 12

    Russo, C. et al. Pyroglutamate-modified amyloid β-peptides—AβN3(pE)—strongly affect cultured neuron and astrocyte survival. J. Neurochem. 82, 1480–1489 (2002)

    CAS  Article  Google Scholar 

  13. 13

    Schilling, S. et al. On the seeding and oligomerization of pGlu-amyloid peptides (in vitro). Biochemistry 45, 12393–12399 (2006)

    CAS  Article  Google Scholar 

  14. 14

    Schlenzig, D. et al. Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 48, 7072–7078 (2009)

    CAS  Article  Google Scholar 

  15. 15

    Levine, H., III Thioflavine T interaction with synthetic Alzheimer’s disease β-amyloid peptides: detection of amyloid aggregation in solution. Protein Sci. 2, 404–410 (1993)

    MathSciNet  CAS  Article  Google Scholar 

  16. 16

    Wang, X. M. et al. A new microcellular cytotoxicity test based on calcein AM release. Hum. Immunol. 37, 264–270 (1993)

    CAS  Article  Google Scholar 

  17. 17

    Scudiero, D. A. et al. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res. 48, 4827–4833 (1988)

    CAS  PubMed  Google Scholar 

  18. 18

    Alexandru, A. et al. Selective hippocampal neurodegeneration in transgenic mice expressing small amounts of truncated Aβ is induced by pyroglutamate–Aβ formation. J. Neurosci. 31, 12790–12801 (2011)

    CAS  Article  Google Scholar 

  19. 19

    Tucker, K. L., Meyer, M. & Barde, Y. A. Neurotrophins are required for nerve growth during development. Nature Neurosci. 4, 29–37 (2001)

    CAS  Article  Google Scholar 

  20. 20

    Rockenstein, E., Mallory, M., Mante, M., Sisk, A. & Masliaha, E. Early formation of mature amyloid-β protein deposits in a mutant APP transgenic model depends on levels of Aβ1–42 . J. Neurosci. Res. 66, 573–582 (2001)

    CAS  Article  Google Scholar 

  21. 21

    Jawhar, S. et al. Overexpression of glutaminyl cyclase, the enzyme responsible for pyroglutamate Aβ formation, induces behavioral deficits, and glutaminyl cyclase knock-out rescues the behavioral phenotype in 5XFAD mice. J. Biol. Chem. 286, 4454–4460 (2011)

    CAS  Article  Google Scholar 

  22. 22

    Tanghe, A. et al. Pathological hallmarks, clinical parallels, and value for drug testing in Alzheimer’s disease of the APP[V717I] London transgenic mouse model. Int. J. Alzheimers Dis. 2010, (2010)

  23. 23

    Wilcock, D. M. et al. Progression of amyloid pathology to Alzheimer’s disease pathology in an amyloid precursor protein transgenic mouse model by removal of nitric oxide synthase 2. J. Neurosci. 28, 1537–1545 (2008)

    CAS  Article  Google Scholar 

  24. 24

    He, W. & Barrow, C. J. The Aβ 3-pyroglutamyl and 11-pyroglutamyl peptides found in senile plaque have greater β-sheet forming and aggregation propensities in vitro than full-length Aβ. Biochemistry 38, 10871–10877 (1999)

    CAS  Article  Google Scholar 

  25. 25

    Wirths, O. et al. Intraneuronal pyroglutamate-Aβ 3–42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathol. 118, 487–496 (2009)

    Article  Google Scholar 

  26. 26

    Güntert, A., Dobeli, H. & Bohrmann, B. High sensitivity analysis of amyloid-β peptide composition in amyloid deposits from human and PS2APP mouse brain. Neuroscience 143, 461–475 (2006)

    Article  Google Scholar 

  27. 27

    Piccini, A. et al. β-Amyloid is different in normal aging and in Alzheimer disease. J. Biol. Chem. 280, 34186–34192 (2005)

    CAS  Article  Google Scholar 

  28. 28

    Hartlage-Rübsamen, M. et al. Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 121, 705–719 (2011)

    Article  Google Scholar 

  29. 29

    Vossel, K. A. et al. Tau reduction prevents Aβ-induced defects in axonal transport. Science 330, 198 (2010)

    ADS  CAS  Article  Google Scholar 

  30. 30

    Wilcox, K. C., Lacor, P. N., Pitt, J. & Klein, W. L. Aβ oligomer-induced synapse degeneration in Alzheimer’s disease. Cell. Mol. Neurobiol. 31, 939–948 (2011)

    CAS  Article  Google Scholar 

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The authors are grateful for support from the following sources: the Alzheimer’s Association (grant 4079 to G.S.B.); the Owens Family Foundation (G.S.B.); the Cure Alzheimer’s Fund (G.S.B., C.G.G.); NIH/NIGMS training grant T32 GM008136, which funded part of J.M.N.’s PhD training; NIH/NIA grant R01 AG033069 (C.G.G.); and the German Federal Department of Science and Technology grant 03IS2211F (H.-U.D.). Funding for the UCI-ADRC was provided by NIH/NIA grant P50 AG16573. We also thank H. Dawson and M. Vitek of Duke University for providing the tau-knockout mice. This work fulfilled part of the requirements for the PhD earned by J.M.N. at the University of Virginia. The technical assistance of A. Spano, H.-H. Ludwig, E. Scheel and K. Schulz is gratefully acknowledged.

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J.M.N. performed most of the biochemical and cell biological experiments; S.S. was the principal force behind the experiments involving hAPPSL/hQC and TBA2.1/tau-knockout mice, and was aided by B.H.-P. and H.C.; A.S. and T.W. fractionated and analysed human brain extracts; E.S., K.T. and B.W. performed the peri-hippocampal injection experiments; A.H. and C.G.G. produced and characterized the M64 and M87 antibodies; R.R. and K.R. performed the electrophysiology experiments; A.A., W.J. and S.G. performed and analysed the immunohistochemical experiments on TBA2.1 and tau-knockout/TBA2.1 mice; G.S.B. and H.-U.D. initiated and directed the project; G.S.B. was the principal writer of the paper; all of the authors participated in the design and analysis of experiments, and in editing of the paper.

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Correspondence to Hans-Ulrich Demuth or George S. Bloom.

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The authors declare no competing financial interests.

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Nussbaum, J., Schilling, S., Cynis, H. et al. Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β. Nature 485, 651–655 (2012).

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