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Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3β kinase: implications for Alzheimer’s disease

Molecular Psychiatry volume 22, pages 1002–1008 (2017)Cite this article

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Abstract

The pathological hallmark of Alzheimer’s disease (AD) is accumulation of misfolded amyloid-β peptides and hyperphosphorylated tau protein in the brain. Increasing evidence suggests that serine-aspartyl proteases—caspases are activated in the AD brain. Previous studies identified a caspase-3 cleavage site within the amyloid-β precursor protein, and a caspase-3 cleavage of tau as the mechanisms involved in the development of Aβ and tau neuropathology, respectively. However, the potential role that caspase-3 could have on tau metabolism remains unknown. In the current studies, we provide experimental evidence that caspase-3 directly and specifically regulates tau phosphorylation, and demonstrate that this effect is mediated by the GSK3β kinase pathway via a caspase-3-dependent cleavage of the protein kinase B (also known as Akt). In addition, we confirm these results in vivo by using a transgenic mouse model of AD. Collectively, our findings demonstrate a new role for caspase-3 in the neurobiology of tau, and suggest that therapeutic strategies aimed at inhibiting this protease-dependent cleavage of Akt may prove beneficial in preventing tau hyperphosphorylation and subsequent neuropathology in AD and related tauopathies.

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Acknowledgements

This work was in part supported by a grant from the Alzheimer Art Quilt Initiative and the Wanda Simone Endowment for Neuroscience.

Author contributions

JC and DP designed the experiments. JC and EL performed the experiments. JC and DP wrote the manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    J Chu, E Lauretti & D Praticò

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  1. J Chu
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  3. D Praticò
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Correspondence to D Praticò.

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Chu, J., Lauretti, E. & Praticò, D. Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3β kinase: implications for Alzheimer’s disease. Mol Psychiatry 22, 1002–1008 (2017). https://doi.org/10.1038/mp.2016.214

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