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Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change

Nature Neuroscience volume 16, pages 587–595 (2013)Cite this article

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Abstract

Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-β Aβ40 and Aβ42 isoforms is central to familial Alzheimer's disease (FAD) pathogenesis. However, FAD mutations account for only 1–2% of Alzheimer's disease cases, leaving the experience-dependent mechanisms regulating Aβ40/42 an enigma. Here we explored regulation of Aβ40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aβ40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aβ40 production. Conversely, single spikes did not alter basal PS1 conformation and Aβ40/42. Burst-induced PS1 conformational shift was mediated by means of Ca2+-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and Aβ40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aβ40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.

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Figure 1: Differential regulation of Aβ40 and Aβ42 isoforms by temporal pattern of afferent input in acute hippocampal slices.
Figure 2: Dependency of Aβ40 and Aβ42 isoforms on postsynaptic activation.
Figure 3: Spike bursts induce PS1 conformational changes in hippocampal neurons.
Figure 4: Dependency of PS1 conformation and Aβ40/42 on synaptic vesicle recycling.
Figure 5: Ca2+ dependency of PS1 conformational changes and Aβ40/42 augmentation induced by bursts.
Figure 6: Synaptic facilitation bidirectionally regulates Aβ40/42 augmentation by bursts in hippocampal slices.
Figure 7: Dark rearing enhances synaptic and Aβ40 facilitation by bursts in CA3–CA1 hippocampal connections.
Figure 8: Correlation between short-term plasticity in CA3–CA1 synaptic connections and dynamics of Aβ isoforms per individual animal across different experimental conditions.

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Acknowledgements

We thank B. De Strooper for discussions, O. Berezovska (Harvard Medical School) for providing GFP-PS1-RFP cDNA, S. Frere for comments on the manuscript, Y. Amitai for suggestions on an early version of the manuscript and all laboratory members for discussions. This work was supported by European Research Council (281403), Legacy Heritage Biomedical Program of the Israel Science Foundation (1925/08), Alzheimer's Association (NIRG-10-172308) and Israel Science Foundation (993/08 and 170/08) grants to I.S. and EUROSPIN and SynSys Consortia (FP7-HEALTH-F2-2009-241498 and FP7-HEALTH-F2-2009-242167) grants to N.B. I.D. is grateful to the Center for Nanoscience and Nanotechnology of Tel Aviv University and Azrieli Foundation for the award of doctoral fellowships.

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  1. Iftach Dolev and Hilla Fogel: These authors equally contributed to this work.

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Iftach Dolev, Hilla Fogel, Hila Milshtein, Yevgeny Berdichevsky, Neta Gazit & Inna Slutsky

  2. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Hila Milshtein, Neta Gazit & Inna Slutsky

  3. Department of Molecular Neurobiology, Max Planck Institute for Experimental Medicine, Göttingen, Germany

    Noa Lipstein & Nils Brose

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  1. Iftach Dolev
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Contributions

I.D. designed, performed, analyzed and interpreted biochemical and electrophysiological experiments. H.F. designed, performed, analyzed and interpreted FRET and FM experiments. H.M. and N.G. performed and analyzed whole-cell voltage-clamp recordings. Y.B. helped to conduct western blot experiments. N.L. and N.B. provided Munc13-1/2 double knockout mice and assisted with the interpretation of results. I.S. designed the study, interpreted the results and supervised the project. I.S., I.D. and H.F. wrote the manuscript.

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Correspondence to Inna Slutsky.

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Dolev, I., Fogel, H., Milshtein, H. et al. Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change. Nat Neurosci 16, 587–595 (2013). https://doi.org/10.1038/nn.3376

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