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Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease

Nature volume 451, pages 720–724 (2008)Cite this article

Abstract

Senile plaques accumulate over the course of decades in the brains of patients with Alzheimer’s disease. A fundamental tenet of the amyloid hypothesis of Alzheimer’s disease is that the deposition of amyloid-β precedes and induces the neuronal abnormalities that underlie dementia1. This idea has been challenged, however, by the suggestion that alterations in axonal trafficking and morphological abnormalities precede and lead to senile plaques2. The role of microglia in accelerating or retarding these processes has been uncertain. To investigate the temporal relation between plaque formation and the changes in local neuritic architecture, we used longitudinal in vivo multiphoton microscopy to sequentially image young APPswe/PS1d9xYFP (B6C3-YFP) transgenic mice3. Here we show that plaques form extraordinarily quickly, over 24 h. Within 1–2 days of a new plaque’s appearance, microglia are activated and recruited to the site. Progressive neuritic changes ensue, leading to increasingly dysmorphic neurites over the next days to weeks. These data establish plaques as a critical mediator of neuritic pathology.

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Figure 1: Appearance of a novel plaque is a rapid process.
Figure 2: Microglia recruitment follows plaque formation.
Figure 3: Plaque formation has no immediate effect on neuritic curvature.

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Acknowledgements

This work was supported by a grant from the National Institutes of Health and an award from the Alzheimer’s Association. We also thank S. Freeman (Harvard Medical School, Boston) for technical advice and W. E. Klunk (University of Pittsburgh) for the gift of methoxy-XO4.

Author Contributions M.M.-L. and B.T.H. designed the study; M.M.-L., T.L.S.-J., C.P., M.G.-A., A.de C. and A.R. performed experiments; J.K.-T. and D.M.H. provided mice; M.M.-L. and B.T.H. wrote the manuscript; B.J.B. gave technical support and conceptual advice; B.T.H. supervised the study.

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Authors and Affiliations

  1. Department of Neurology, Alzheimer’s Disease Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129, USA,

    Melanie Meyer-Luehmann, Tara L. Spires-Jones, Claudia Prada, Monica Garcia-Alloza, Alix de Calignon, Anete Rozkalne, Brian J. Bacskai & Bradley T. Hyman

  2. Department of Neurology, Washington University School of Medicine, St Louis, Missouri 63110, USA,

    Jessica Koenigsknecht-Talboo & David M. Holtzman

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  1. Melanie Meyer-Luehmann
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Correspondence to Bradley T. Hyman.

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Meyer-Luehmann, M., Spires-Jones, T., Prada, C. et al. Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease. Nature 451, 720–724 (2008). https://doi.org/10.1038/nature06616

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