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Extracellular amyloid formation and associated pathology in neural grafts

Nature Neuroscience volume 6, pages 370–377 (2003)Cite this article

Abstract

Amyloid precursor protein (APP) processing and the generation of β-amyloid peptide (Aβ) are important in the pathogenesis of Alzheimer's disease. Although this has been studied extensively at the molecular and cellular levels, much less is known about the mechanisms of amyloid accumulation in vivo. We transplanted transgenic APP23 and wild-type B6 embryonic neural cells into the neocortex and hippocampus of both B6 and APP23 mice. APP23 grafts into wild-type hosts did not develop amyloid deposits up to 20 months after grafting. In contrast, both transgenic and wild-type grafts into young transgenic hosts developed amyloid plaques as early as 3 months after grafting. Although largely diffuse in nature, some of the amyloid deposits in wild-type grafts were congophilic and were surrounded by neuritic changes and gliosis, similar to the amyloid-associated pathology previously described in APP23 mice. Our results indicate that diffusion of soluble Aβ in the extracellular space is involved in the spread of Aβ pathology, and that extracellular amyloid formation can lead to neurodegeneration.

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Figure 1: Neural grafting of APP23 tissue into B6 hosts.
Figure 2: APP and Aβ levels in APP23 grafts placed in B6 hosts.
Figure 3: Neural grafting of APP23 and B6 tissue into APP23 hosts.
Figure 4: Amyloid in B6 grafts.
Figure 5: Neural grafting of B6 tissue into thalamus and striatum of APP23 hosts.
Figure 6: Mechanism of amyloid formation in B6 grafts.
Figure 7: Amyloid pathology associated with congophilic amyloid plaques in B6 grafts.

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Acknowledgements

The authors thank S. Schmidt (New York, USA) for the advice with ELISA, and D. Ingram (Baltimore, USA), S. Brandner and A. Aguzzi (Zürich, Switzerland) for help with the grafting procedure. Furthermore, we thank L. Walker (Ann Arbor, USA), M. Calhoun (New York, USA), S. Sisodia (Chicago, USA), E. Sykova (Prague, Czech Republic), T. Saido (Saitama, Japan), M. Leissring (Boston, USA), G. Multhaup and T. Hartmann (Heidelberg, Germany), A. Probst, M. Tolnay, A. Renken, and D. Monard (Basel, Switzerland) for advice, help and comments on this manuscript. This work has been supported by grants from the American Health Assistance Foundation (Alzheimer's disease program), the Horten Foundation (Madonna del Piano, Switzerland), the AETAS Foundation (Geneva, Switzerland) and the Swiss National Science Foundation.

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Author notes

  1. Melanie Meyer-Luehmann and Martina Stalder: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Neuropathology, Institute of Pathology, University of Basel, Schönbeinstrasse 40, Basel, CH-4003, Switzerland

    Melanie Meyer-Luehmann, Martina Stalder, Martin C. Herzig, Stephan A. Kaeser, Esther Kohler, Michelle Pfeifer, Sonia Boncristiano & Mathias Jucker

  2. Nathan Kline Institute for Psychiatric Research, New York University School of Medicine, Orangeburg, 10962, New York, USA

    Paul M. Mathews

  3. Johnson and Johnson Pharmaceutical Research and Development, Beerse, B-2340, Belgium

    Marc Mercken

  4. Novartis Pharma AG, Nervous System Research, Basel, CH-4002, Switzerland

    Dorothee Abramowski & Matthias Staufenbiel

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Correspondence to Mathias Jucker.

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Meyer-Luehmann, M., Stalder, M., Herzig, M. et al. Extracellular amyloid formation and associated pathology in neural grafts. Nat Neurosci 6, 370–377 (2003). https://doi.org/10.1038/nn1022

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