title: Treatment of intermittent hypoxia increases phosphorylated tau in the hippocampus via biological processes common to aging.
abstract: Sleep-disordered breathing produces cognitive impairments, and is possibly associated with Alzheimer disease (AD). Intermittent hypoxia treatment (IHT), an experimental model for sleep-disordered breathing, results in cognitive impairments in animals via unknown mechanisms. Here, we exposed mice to IHT protocols, and performed biochemical analyses and microarray analyses regarding their hippocampal samples. In particular, we performed gene ontology (GO)-based microarray analysis to elucidate effects of IHT on hippocampal functioning, which were compared with the effects of various previously-reported experimental conditions on that (ref. Gene Expression Omnibus, The National Center for Biotechnology Information). Our microarray analyses revealed that IHT and aging shared alterations in some common GO, which were also observed with kainic acid treatment, Dicer ablation, or moderate glutamate excess. Mapping the altered genes using the Kyoto Encyclopedia of Genes and Genomes PATHWAY database indicated that IHT and aging affected several pathways including "MAPK signaling pathway", "PI3K-Akt signaling pathway", and "glutamatergic synapse". Consistent with the gene analyses, in vivo analyses revealed that IHT increased phosphorylated tau, reflecting an imbalance of kinases and/or phosphatases, and reduced proteins relevant to glutamatergic synapses. In addition, IHT increased phosphorylated p70 S6 kinase, indicating involvement of the mammalian target of rapamycin signaling pathway. Furthermore, IHT mice demonstrated hyperactivity in Y-maze tests, which was also observed in AD models. We obtained important data or something from the massive amount of microarray data, and confirmed the validity by in vivo analyses: the IHT-induced cognitive impairment may be partially explained by the fact that IHT increases phosphorylated tau via biological processes common to aging. Moreover, as aging is a major risk factor for AD, IHT is a novel model for investigating the pathological processes contributing to AD onset.
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan. syagi@saitama-med.ac.jp.|Present address: Department of Peripheral Nervous System Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8502, Japan. syagi@saitama-med.ac.jp.
authors.forename: Sosuke
authors.initials: S
authors.lastname: Yagishita
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.|Faculty of Health and Medical Care, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan.
authors.forename: Seiya
authors.initials: S
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Yoshikawa
authors.affiliation: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Iida
authors.affiliation: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Hirata
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.|Faculty of Health and Medical Care, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1241, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Life Science, Faculty of Science, Gakushuin University, 1-5-1 Mejiro, Toshima-ku, Tokyo, 171-8588, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Genomic Drug Discovery Science, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan. akira_h@pharm.kyoto-u.ac.jp.
authors.forename: Akira
authors.initials: A
authors.lastname: Hirasawa
authors.affiliation: Department of Pharmacology, Faculty of Medicine, Saitama Medical University, 38 Moro-hongo, Moroyama-machi, Iruma-gun, Saitama, 350-0495, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Awaji
mesh_terms: D000375:Aging / Q000473:pathology*; D000818:Animals; D063990:Gene Ontology; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D018782:Maze Learning; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D025341:Principal Component Analysis; D013569:Synapses / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016875:tau Proteins
keywords: Alzheimer disease; Gene ontology-based microarray analysis; Intermittent hypoxia; Sleep-disordered breathing; Tau