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Amyloid beta from axons and dendrites reduces local spine number and plasticity

Nature Neuroscience volume 13, pages 190–196 (2010)Cite this article

Abstract

Excessive synaptic loss is thought to be one of the earliest events in Alzheimer's disease. Amyloid beta (Aβ), a peptide secreted in an activity-modulated manner by neurons, has been implicated in the pathogenesis of Alzheimer's disease by removing dendritic spines, sites of excitatory synaptic transmission. However, issues regarding the subcellular source of Aβ, as well as the mechanisms of its production and actions that lead to synaptic loss, remain poorly understood. In rat organotypic slices, we found that acute overproduction of either axonal or dendritic Aβ reduced spine density and plasticity at nearby (∼5–10 μm) dendrites. The production of Aβ and its effects on spines were sensitive to blockade of action potentials or nicotinic receptors; the effects of Aβ (but not its production) were sensitive to NMDA receptor blockade. Notably, only 30–60 min blockade of Aβ overproduction permitted induction of plasticity. Our results indicate that continuous overproduction of Aβ at dendrites or axons acts locally to reduce the number and plasticity of synapses.

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Figure 1: Dendritic Aβ reduces local spine density in an activity-dependent manner.
Figure 2: Axonal Aβ reduces local spine density in an activity-dependent manner.
Figure 3: Aβ secretion is sensitive to blockade of action potentials or nAChRs, but not to blockade of NMDA receptors.
Figure 4: Synthetic Aβ-induced spine loss can be rescued by blockade of NMDA receptors, but not by blockade of action potentials or nAChRs.
Figure 5: Acute overproduction of Aβ reduces spine structural plasticity by NMDAR- and nAChR-dependent mechanisms.
Figure 6: Axonal secretion of Aβ reduces local spine structural plasticity.
Figure 7: Dendritic secretion of Aβ reduces local spine structural plasticity.

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Acknowledgements

We thank members of the Malinow laboratory for helpful discussions, J. Huang for careful reading of the manuscript and N. Dawkins and I. Hunton for expert technical assistance. This work was supported by grants from the US National Institutes of Health (R.M.), the Cure Alzheimer's Fund (R.M.), Eisai (H.H.) and the Leslie C. Quick Fellowship (W.W.).

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  1. Wei Wei

    Present address: Present address: Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, California, USA.,

Authors and Affiliations

  1. Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA

    Wei Wei & Roberto Malinow

  2. Departments of Neuroscience and Biology, Center for Neural Circuits and Behavior, University of California, San Diego, La Jolla, California, USA

    Louis N Nguyen, Helmut W Kessels, Hiroaki Hagiwara & Roberto Malinow

  3. Department of Neurobiology, University of Chicago, Chicago, Illinois, USA

    Sangram Sisodia

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Contributions

W.W., L.N.N., H.W.K. and H.H. designed and conducted the experiments and analyzed data. S.S. and R.M. designed experiments and supervised the project.

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Correspondence to Roberto Malinow.

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Wei, W., Nguyen, L., Kessels, H. et al. Amyloid beta from axons and dendrites reduces local spine number and plasticity. Nat Neurosci 13, 190–196 (2010). https://doi.org/10.1038/nn.2476

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