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Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation

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Abstract

Glycogen synthase kinase-3β (GSK-3β) is a key element to phosphorylate tau and form neurofibrillary tangles (NFTs) found in tauopathies including Alzheimer’s disease (AD). A current topic for AD therapy is focused upon how to prevent tau phosphorylation. In the present study, PKCε activated Akt and inactivated GSK-3β by directly interacting with each protein. Inhibition of protein tyrosine phosphatase 1B (PTP1B), alternatively, caused an enhancement in the tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), allowing activation of Akt through a pathway along an IRS-1/phosphatidylinositol 3 kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, to phosphorylate and inactivate GSK-3β. Combination of PKCε activation and PTP1B inhibition more sufficiently activated Akt and inactivated GSK-3β than each independent treatment, to suppress amyloid β (Aβ)-induced tau phosphorylation and ameliorate spatial learning and memory impairment in 5xFAD transgenic mice, an animal model of AD. This may represent an innovative strategy for AD therapy.

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Authors and Affiliations

  1. Division of Bioinformation, Department of Physiology, Hyogo College of Medicine, Nishinomiya, 663-8501, Japan

    Takeshi Kanno, Ayako Tsuchiya & Tomoyuki Nishizaki

  2. Laboratory of Chemical Biology, Advanced Medicinal Research Center, Hyogo University of Health Sciences, Kobe, 650-8530, Japan

    Akito Tanaka

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  1. Takeshi Kanno
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  2. Ayako Tsuchiya
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  3. Akito Tanaka
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  4. Tomoyuki Nishizaki
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Correspondence to Tomoyuki Nishizaki.

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Kanno, T., Tsuchiya, A., Tanaka, A. et al. Combination of PKCε Activation and PTP1B Inhibition Effectively Suppresses Aβ-Induced GSK-3β Activation and Tau Phosphorylation. Mol Neurobiol 53, 4787–4797 (2016). https://doi.org/10.1007/s12035-015-9405-x

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  • DOI: https://doi.org/10.1007/s12035-015-9405-x

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