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Aβ1–42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β

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Abstract

Amyloid-β1–42 (Aβ) is thought to be a major mediator of the cognitive deficits in Alzheimer's disease. The ability of Aβ to inhibit hippocampal long-term potentiation provides a cellular correlate of this action, but the underlying molecular mechanism is only partially understood. We found that a signaling pathway involving caspase-3, Akt1 and glycogen synthase kinase-3β is an important mediator of this effect in rats and mice.

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Figure 1: Identification of a role for caspases in Aβ inhibition of LTP.
Figure 2: Caspase-3 and cleavage of Akt1 are involved in the Aβ inhibition of LTP.
Figure 3: Aβ inhibition of LTP is reversed by blockade of GSK-3.

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Acknowledgements

This work was funded by the UK Alzheimer's Research Trust (K.C.), Biotechnology and Biological Sciences Research Council (K.C.), Medical Research Council (G.L.C.) and The Royal Society (J.J.). G.L.C. is a World Class University International Scholar and D.J.W. is an UK Alzheimer's Research Trust–funded Ph.D. student.

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Author notes

  1. Jihoon Jo and Daniel J Whitcomb: These authors contributed equally to this work.

Authors and Affiliations

  1. Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, Faculty of Medicine and Dentistry, University of Bristol, Bristol, UK

    Jihoon Jo, Daniel J Whitcomb, Talitha L Kerrigan, Gilles Bru-Mercier, Bryony Dickinson, Sarah Scullion & Kwangwook Cho

  2. Department of Neuroscience, Genentech Inc., South San Francisco, California, USA

    Kimberly Moore Olsen, Shih-Ching Lo & Morgan Sheng

  3. MRC Centre for Synaptic Plasticity, University of Bristol, Bristol, UK

    Sarah Scullion, Graham Collingridge & Kwangwook Cho

  4. School of Physiology and Pharmacology, University of Bristol, Bristol, UK

    Graham Collingridge

Authors
  1. Jihoon Jo
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  2. Daniel J Whitcomb
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  3. Kimberly Moore Olsen
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  4. Talitha L Kerrigan
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  5. Shih-Ching Lo
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  6. Gilles Bru-Mercier
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  7. Bryony Dickinson
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  8. Sarah Scullion
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  9. Morgan Sheng
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  10. Graham Collingridge
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  11. Kwangwook Cho
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Contributions

The study was conceived by K.C. The experiments were designed by K.C., M.S. and G.L.C. and carried out by J.J., D.J.W., K.M.O., T.L.K., J.S.L., G.B., B.D. and S.S. The manuscript was written by G.L.C., M.S. and K.C.

Corresponding author

Correspondence to Kwangwook Cho.

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Competing interests

K.M.O., S.-C.L. and M.S. are employees of Genentech.

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Supplementary Figures 1, 2 and Supplementary Methods (PDF 368 kb)

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Jo, J., Whitcomb, D., Olsen, K. et al. Aβ1–42 inhibition of LTP is mediated by a signaling pathway involving caspase-3, Akt1 and GSK-3β. Nat Neurosci 14, 545–547 (2011). https://doi.org/10.1038/nn.2785

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  • DOI: https://doi.org/10.1038/nn.2785

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