Treatment of intermittent hypoxia increases phosphorylated tau in the hippocampus via biological processes common to aging

Sosuke Yagishita, Seiya Suzuki, Keisuke Yoshikawa, Keiko Iida, Ayako Hirata, Masahiko Suzuki, Akihiko Takashima, Kei Maruyama, Akira Hirasawa, Takeo Awaji

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.