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Aβ seeds resist inactivation by formaldehyde

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Abstract

Cerebral β-amyloidosis can be exogenously induced by the intracerebral injection of brain extracts containing aggregated β-amyloid (Aβ) into young, pre-depositing Aβ precursor protein- (APP) transgenic mice. Previous work has shown that the induction involves a prion-like seeding mechanism in which the seeding agent is aggregated Aβ itself. Here we report that the β-amyloid-inducing activity of Alzheimer’s disease (AD) brain tissue or aged APP-transgenic mouse brain tissue is preserved, albeit with reduced efficacy, after formaldehyde fixation. Moreover, spectral analysis with amyloid conformation-sensitive luminescent conjugated oligothiophene dyes reveals that the strain-like properties of aggregated Aβ are maintained in fixed tissues. The resistance of Aβ seeds to inactivation and structural modification by formaldehyde underscores their remarkable durability, which in turn may contribute to their persistence and spread within the body. The present findings can be exploited to establish the relationship between the molecular structure of Aβ aggregates and the variable clinical features and disease progression of AD even in archived, formalin-fixed autopsy material.

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Acknowledgments

We would like to thank Matthias Staufenbiel for the APP23 tg mice and comments on the manuscript; Markus Fändrich (Ulm, Germany) for the recombinant Aβ; Yvonne Eisele, Jan Winchenbach, Maria Mina, Christian Krüger, Ulrike Obermüller, Jörg Odenthal, Jeromy Dooyema, Sofie Nyström and many other members of our departments for experimental help and discussions. The assistance of Jay Rasmussen (Lethbridge, Canada) and Rodrigo Morales (Houston, USA) is greatly appreciated. This work was supported by grants from the Competence Network on Degenerative Dementias (BMBF-01GI0705), the National Institutes of Health (R21AG040589, P51RR165, P51OD11132 and R36AG043646), the MetLife Foundation, and by the Swedish Research Council.

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Authors and Affiliations

  1. German Center for Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany

    Sarah K. Fritschi, Lan Ye, Jasmin Mahler, Anika Bühler, Frank Baumann, Manuela Neumann & Mathias Jucker

  2. Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany

    Sarah K. Fritschi, Lan Ye, Jasmin Mahler, Anika Bühler, Frank Baumann & Mathias Jucker

  3. Graduate School of Cellular and Molecular Neuroscience, University of Tübingen, 72074, Tübingen, Germany

    Sarah K. Fritschi, Lan Ye & Jasmin Mahler

  4. Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30329, USA

    Amarallys Cintron & Lary C. Walker

  5. Department of Neurology, Emory University, Atlanta, GA, 30322, USA

    Lary C. Walker

  6. Department of Neuropathology, University of Tübingen, 72076, Tübingen, Germany

    Manuela Neumann

  7. Department of Chemistry, IFM, Linköping University, 581 83, Linköping, Sweden

    K. Peter R. Nilsson & Per Hammarström

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  1. Sarah K. Fritschi
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  2. Amarallys Cintron
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  10. Lary C. Walker
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  11. Mathias Jucker
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Corresponding authors

Correspondence to Lary C. Walker or Mathias Jucker.

Additional information

S. K. Fritschi and A. Cintron contributed equally.

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Fritschi, S.K., Cintron, A., Ye, L. et al. Aβ seeds resist inactivation by formaldehyde. Acta Neuropathol 128, 477–484 (2014). https://doi.org/10.1007/s00401-014-1339-2

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  • DOI: https://doi.org/10.1007/s00401-014-1339-2

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