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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.

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  • 30 May 2012

    Further grant information was added to Acknowledgements.


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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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Authors and Affiliations



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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