We have published a paper on a novel model for dementia research.

Reference:
Authors: Sosuke Yagishita*, Seiya Suzuki, Keisuke Yoshikawa, Keiko Iida, Ayako Hirata, Masahiko Suzuki, Akihiko Takashima, Kei Maruyama, Akira Hirasawa*, Takeo Awaji (* corresponding authors)
Title：Treatment of intermittent hypoxia increases phosphorylated tau in the hippocampus via biological processes common to aging
Molecular Brain, 2017, 10:2
URL: https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-016-0282-7

[Summary]
(1) Treatment of intermittent hypoxia and aging shared common biological processes.
(2) Treatment of intermittent hypoxia increases phosphorylated tau.

[Background]
Alzheimer disease (AD) is the most common type of dementia, and the neuropathological hallmarks of AD are depositions of amyloid  protein and hyperphosphorylated tau. It has been reported that aging is the major risk factor of AD, but there has been few models to research the relationship between aging and the onset of AD. In this study, we focused on an experimental model of sleep-disordered breathing, i.e., intermittent hypoxia treatment (IHT), since several clinical studies have suggested the close relationship between sleep-disordered breathing and dementia. We performed in vivo and in silico analyses using hippocampus of IHT model.

[Method]
The IHT group was exposed to a protocol of 1 min of pure N2 injection, in order to reduce the fraction of inspired O2 (FIO2) from 21% to 5%, followed by 2 min of room air injection to increase FIO2 from 5% to 21%. This 3 min cycle was repeated for 8 h each day.

[Results]
(1) Common biological processes between IHT and aging.
In order to understand the effects of IHT on hippocampal functioning, microarray analysis was performed using data of IHT-exposed mice. We also analysed data derived from mice reared for 12 months (aging). We found that IHT and aging shared common biological processes. We then compared our experimental data with the various data stored in public database. We found that IHT, Dicer ablation, and moderate excess of neuronal activity had common biological processes (Figure 1).

 

(2) IHT led to an increase in phosphorylated tau.
As hyperphosphorylated tau accumulates in AD brains, we focused on tau phosphorylation. We investigated whether IHT affect the level of phosphorylated tau.
We found that IHT significantly led to an increase in phosphorylated tau (Figure 2). This result was consistent with a previous report showing that Dicer ablation (similar gene expression pattern with IHT, as shown in Figure 1) led to increase in phosphorylated tau.

(3) Supplement
(1) Mice exposed to IHT for 5 days showed hyperactivity in Y-maze tests. This result was consistent with previous-reported AD models.
(2) Elongation of the IHT periods to 28 days resulted in decreases in postsynaptic proteins.

[Discussion]
(1) A novel model for dementia research
We found that IHT and aging share common biological processes. Aging is a major risk factor for AD, and IHT may mimic an environmental stimulus that contributes to AD progression. Thus IHT is a novel model for investigating the pathological processes contributing to AD onset. Moreover, since the IHT experiment is an inexpensive way, this is a good model to research effectively on a limited budget.

(2) The potential link between sleep-disordered breathing and AD
Several clinical studies have suggested the close relationship between sleep-disordered breathing and AD. Of course, an increase in phosphorylated tau dose NOT mean progression of AD onset. However, the fact that IHT led to an increase in phosphorylated tau may be the first experimental evidence that could partially explained the potential link between sleep-disordered breathing and AD.