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The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain

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Abstract

The deposition of the β-amyloid (Aβ) peptide in senile plaques and cerebral Aβ-amyloid angiopathy can be seeded in β-amyloid precursor protein (APP)-transgenic mice by the intracerebral infusion of brain extracts containing aggregated Aβ. Previous studies of seeded β-amyloid induction have used relatively short incubation periods to dissociate seeded β-amyloid induction from endogenous β-amyloid deposition of the host, thus precluding the analysis of the impact of age and extended incubation periods on the instigation and spread of Aβ lesions in brain. In the present study using R1.40 APP-transgenic mice (which do not develop endogenous Aβ deposition up to 15 months of age) we show that: (1) seeding at 9 months of age does not induce more Aβ deposition than seeding at 3 months of age, provided that the incubation period (6 months) is the same; and (2) very long-term (12 months) incubation after a focal application of the seed results in the emergence of Aβ deposits throughout the forebrain. These findings indicate that the presence of Aβ seeds, and not the age of the host per se, is critical to the initiation of Aβ aggregation in the brain, and that Aβ deposition, actuated in one brain area, eventually spreads throughout the brain.

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Acknowledgments

This work was supported by grants from the Competence Network on Degenerative Dementias (BMBF-01GI0705), the BMBF in the frame of ERA-Net NEURON (MIPROTRAN), NIH RR-00165, P50AG025688, the Alzheimer’s Association (NIRG-10-173099) and the CART Foundation. TH is recipient of a postdoctoral fellowship from the Alexander von Humboldt Foundation (Bonn, Germany). We gratefully acknowledge helpful discussions and experimental help of Franziska Langer, Götz Heilbronner, Ulrike Obermüller, Jörg Odenthal, Stephan Kaeser, Michael Hruscha and Andrea Bosch (Tübingen, Germany) and Harry LeVine III (Lexington, KY, USA).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Tsuyoshi Hamaguchi, Yvonne S. Eisele, Nicholas H. Varvel & Mathias Jucker

  2. DZNE, German Center for Neurodegenerative Diseases, 72076, Tübingen, Germany

    Tsuyoshi Hamaguchi, Yvonne S. Eisele, Nicholas H. Varvel & Mathias Jucker

  3. The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, 44195, USA

    Bruce T. Lamb

  4. Department of Neurology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30322, USA

    Lary C. Walker

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  1. Tsuyoshi Hamaguchi
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  2. Yvonne S. Eisele
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  3. Nicholas H. Varvel
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Correspondence to Mathias Jucker.

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Hamaguchi, T., Eisele, Y.S., Varvel, N.H. et al. The presence of Aβ seeds, and not age per se, is critical to the initiation of Aβ deposition in the brain. Acta Neuropathol 123, 31–37 (2012). https://doi.org/10.1007/s00401-011-0912-1

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  • DOI: https://doi.org/10.1007/s00401-011-0912-1

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