Troglitazone, a thiazolidinedione, decreases tau phosphorylation through the inhibition of cyclin-dependent kinase 5 activity in SH-SY5Y neuroblastoma cells and primary neurons

Authors

  • Du-Hyong Cho,

    1. Department of Neurology, Konkuk University Medical Center, Konkuk University, Seoul, South Korea
    2. Department of Pharmacology, Center for Geriatric Neuroscience Research, SMART Institute of Advanced Biomedical Science School of Medicine, Konkuk University, South Korea
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  • Eun Joo Lee,

    1. Department of Neurology, Konkuk University Medical Center, Konkuk University, Seoul, South Korea
    2. Department of Pharmacology, Center for Geriatric Neuroscience Research, SMART Institute of Advanced Biomedical Science School of Medicine, Konkuk University, South Korea
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  • Kyoung Ja Kwon,

    1. Department of Neurology, Konkuk University Medical Center, Konkuk University, Seoul, South Korea
    2. Department of Pharmacology, Center for Geriatric Neuroscience Research, SMART Institute of Advanced Biomedical Science School of Medicine, Konkuk University, South Korea
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  • Chan Young Shin,

    1. Department of Neurology, Konkuk University Medical Center, Konkuk University, Seoul, South Korea
    2. Department of Pharmacology, Center for Geriatric Neuroscience Research, SMART Institute of Advanced Biomedical Science School of Medicine, Konkuk University, South Korea
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  • Kee-Ho Song,

    1. Department of Internal Medicine, Konkuk University School of Medicine, Seoul, South Korea
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  • Jung-Hyun Park,

    1. Department of Molecular Medicine, Ewha Womans University Medical School, Seoul, South Korea
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  • Inho Jo,

    1. Department of Molecular Medicine, Ewha Womans University Medical School, Seoul, South Korea
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  • Seol-Heui Han

    Corresponding author
    1. Department of Pharmacology, Center for Geriatric Neuroscience Research, SMART Institute of Advanced Biomedical Science School of Medicine, Konkuk University, South Korea
    • Department of Neurology, Konkuk University Medical Center, Konkuk University, Seoul, South Korea
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Address correspondence and reprint requests to Seol-Heui Han, MD, PhD, Department of Neurology, Konkuk University Medical Center and Center for Geriatric Neuroscience Research, SMART Institute of Advanced Biomedical Science, School of Medicine, Konkuk University, 1 Hwayang dong, Gwangjin-gu, Seoul 143-701, Korea. E-mails: alzdoc@kuh.ac.kr; biohyong@hanmail.net

Abstract

The peroxisome proliferator-activated receptor gamma (PPARγ) agonists thiazolidinediones (TZDs) are prescribed for the treatment of type 2 diabetes mellitus. Furthermore, it has been reported that TZDs have a beneficial effect on neurodegenerative disorders, such as Alzheimer's disease. However, the molecular mechanisms underlying this effect are not fully understood. Here, we investigated whether and how troglitazone, a parent TZD drug, inhibits tau phosphorylation. Treatment with troglitazone decreased tau-Thr231 phosphorylation and p35, the specific activator of cyclin-dependent kinase 5 (CDK5), in a dose- and time-dependent manner. Troglitazone also decreased CDK5 enzymatic activity, and ectopic expression of p25, the cleaved and more active form of p35, restored the troglitazone-induced decrease in tau-Thr231 phosphorylation. Treatment with either MG-132, a reversible proteasome inhibitor, or lactacystin, a specific and irreversible 26S proteasome inhibitor, significantly reversed the observed inhibitory effects of troglitazone. However, GW9662, a specific and irreversible PPARγ antagonist, did not alter the observed inhibitory effects. Similar results were also found when other TZD drugs, pioglitazone and rosiglitazone, were used. Treatment with various inhibitors revealed that troglitazone-induced inhibitions of tau-Thr231 phosphorylation and p35 expression were not mediated by glycogen synthase kinase 3β, protein kinase A, and protein phosphatase 2A signaling pathways. Finally, we also found that the same observed inhibitory effects of troglitazone hold true for the use of primary cortical neurons. Taken together, we demonstrated that TZDs repressed tau-Thr231 phosphorylation via the inhibition of CDK5 activity, which was mediated by the proteasomal degradation of p35 and a PPARγ-independent signaling pathway.

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Thiazolidinediones (TZDs) decrease tau-Thr231 phosphorylation via the inhibition of CDK5 enzymatic activity, which is mediated by the enhanced proteasomal degradation of p35 and a PPARγ-independent signaling pathway. This molecular mechanism implies a role for TZD drugs in the prevention and treatment of Alzheimer's disease.

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