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Cited by 427Alzheimer's disease research and treatmentsPrion Diseases and Protein MisfoldingDementia and Cognitive Impairment Research

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

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Nussbaum, Justin M., Schilling, Stephan, Cynis, Holger, Silva, Antonia, Swanson, Eric, Wangsanut, Tanaporn, Tayler, Kaycie, Wiltgen, Brian +10 more·2012·Nature
DOI 10.1038/nature11060PMC PMC3367389
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Abstract

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-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.

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  • Cultured neurons from Tau−/− mice are not susceptible to Aβ-induced synaptic damage and neurotoxicity.

    “Thus, cultured neurons from tau knockout (Tau−/−) mice are not susceptible to Aβ-induced synaptic damage and neurotoxicity (Rapoport et al., 2002; Nussbaum et al., 2012; Zempel et al., 2013) or to Aβ-induced defects in axonal transport (Vossel et al., 2011).”

    From Wild-Type, but Not Mutant N296H, Human Tau Restores Aβ-Mediated Inhibition of LTP in Tau−/− mice (2017) · cites this paper as Nussbaum et al., 2012

    In the passage labeled Abstract (page unavailable in our copy), tau-knockout cultured neurons resisted neurotoxicity from pyroglutamylated Aβ oligomers. The paper also reports synaptic effects, but does not show that tau-knockout cultured neurons are protected from Aβ-induced synaptic damage. Its cultured-neuron finding is specific to the tested Aβ preparations, rather than Aβ generally. (LLM, conf=0.88)

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Cites

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Research works printed but not linked: 28

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Authors
Nussbaum, J. M., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Rönicke, R., Reymann, K., Hutter-Paier, B., Alexandru, A., Jagla, W., Graubner, S., Glabe, C. G., Demuth, H.-U., & Bloom, G. S.
Affiliations
  • University of Virginia (US)
  • Probiodrug (Germany) (DE)
  • University of California, Irvine (US)
  • Leibniz Institute for Neurobiology (DE)
Corresponding author
  • Demuth, Hans-Ulrich
  • Bloom, George S.
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2012-05
Volume
485
Issue
7400
Pages
651-655
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11060
PMC
PMC3367389
OpenAlex
W1974145718
Cited by
427
References
2
Citations by year
2026: 15 · 2025: 22 · 2024: 24 · 2023: 27 · 2022: 21 · 2021: 32 · 2020: 26 · 2019: 28 · 2018: 35 · 2017: 33 · 2016: 38 · 2015: 32 · 2014: 39 · 2013: 38 · 2012: 16
FWCI
25.36
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DZNE Pub (submittedVersion)
Funders
  • National Institute on Aging (P50AG016573, R01AG033069)
  • National Institute of General Medical Sciences (GM008136, T32GM008136)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
prion-like propagation, amyloid-beta oligomers, Alzheimer's disease, amyloid-beta 42, neurofibrillary tangles, amyloid plaques, protein aggregation, post-translational modification
MeSH terms
Alzheimer Disease, Amyloid, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Peptide Fragments, Prions, Amyloid beta-Peptides, tau Proteins, Glutamic Acid, Mutant Proteins, Mice

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