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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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.
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). https://doi.org/10.1038/nature11060
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