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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0282-7) contains supplementary material, which is available to authorized users.

Acute Hypoxia Induced an Imbalanced M1/M2 Activation of Microglia through NF-κB Signaling in Alzheimer’s Disease Mice and Wild-Type Littermates

“…We have previously reported that chronic hypoxia aggravated Aβ production though epigenetic modifications of γ-secretase (Liu et al, 2016 ) and induced autophagy in AD mouse model (Liu et al, 2015 ). Other studies have confirmed that hypoxia could increase tau phosphorylation (Zhang et al, 2014 ; Yagishita et al, 2017 ). Furthermore, our group and others have demonstrated that hypoxia can significantly activate microglia which is believed to play an important role in the pathogenesis of AD (Zhang et al, 2013 ; Sapin et al, 2015 ).…”

“…Hypoxia, as one of the environmental risk factors, was reported to contribute to the pathogenesis of AD (Zhang and Le, 2010 ). Previous studies have indicated that hypoxia may increase Aβ production (Li et al, 2009 ), decrease Aβ degradation (Wang et al, 2011 ) and enhance tau phosphorylation (Gao et al, 2013 ; Yagishita et al, 2017 ), thereafter may further aggravate the pathological changes of AD. Hypoxia is also reported to be associated with neuroinflammation.…”

Impacts of Acute Hypoxia on Alzheimer's Disease-Like Pathologies in APPswe/PS1dE9 Mice and Their Wild Type Littermates

“…Hypoxia has been reported as one of the important environmental risk factors of AD. Many studies have confirmed that hypoxia facilitates AD pathological changes (Shiota et al, 2013 ; Liu et al, 2015 ; Yagishita et al, 2017 ; Zhang et al, 2017 ). In the present study, we demonstrated the impacts of acute hypoxia on AD-like pathologies including Aβ and tau pathologies, dysregulated autophagy, mitochondrial dysfunction and neuroinflammation.…”

Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

“…Although several reports have described biochemical and neurophysiological changes occurring in the hippocampus (Row et al, 2003;Kumar et al, 2009;Xie et al, 2010;Wall et al, 2014;Yagishita et al, 2017), the impact of IH on the dentate gyrus of the hippocampus has been largely been unaddressed. Here we address this issue by examining how IH affects synaptic plasticity and adult neurogenesis in the dentate gyrus.…”