title: Pioglitazone prevents tau oligomerization.
abstract: Tau aggregation and amyloid β protein (Aβ) deposition are the main causes of Alzheimer's disease (AD). Peroxisome proliferator-activated receptor γ (PPARγ) activation modulates Aβ production. To test whether the PPARγ agonist pioglitazone (PIO) is also effective in preventing tau aggregation in AD, we used a cellular model in which wild-type tau protein (4R0N) is overexpressed (M1C cells) (Hamano et al., 2012) as well as primary neuronal cultures. PIO reduced both phosphorylated and total tau levels, and inactivated glycogen synthase kinase 3β, a major tau kinase, associated with activation of Akt. In addition, PIO decreased cleaved caspase3 and C-terminal truncated tau species by caspase, which is expected to decrease tau aggregation. A fractionation study showed that PIO reduced high molecular-weight (120 kDa), oligomeric tau species in Tris Insoluble, sarkosyl-soluble fractions. Tau decrease was reversed by adding GW9662, a PPARγ antagonist. Together, our current results support the idea that PPARγ agonists may be useful therapeutic agents for AD.
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Life Science Innovation Center, University of Fukui, Fukui, Japan. Electronic address: hamano@u-fukui.ac.jp.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Hamano
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Shirafuji
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Chiemi
authors.initials: C
authors.lastname: Makino
authors.affiliation: Department of Neuroscience, Mayo Clinic College Florida, Jacksonville, FL, USA.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Yen
authors.affiliation: Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Kanaan
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Ueno
authors.affiliation: Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Jinya
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ikawa
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsunaga
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Yamamura
authors.affiliation: Brain Attack Ota Memorial Hospital, Fukuyama, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kuriyama
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakamoto
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D008813:Mice, Inbred ICR; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077205:Pioglitazone; D055503:Protein Multimerization / Q000187:drug effects*; D045162:Thiazolidinediones / Q000494:pharmacology*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D016875:tau Proteins; D000077205:Pioglitazone
keywords: Caspase; GSK3β; PPARγ; Phosphorylation; Pioglitazone; Tau; Tau oligomer