Abstract

BackgroundAlzheimer’s disease (AD) is a progressive, degenerative, and terminal disease without cure. There is an urgent need for a new strategy to treat AD. The aim of this study was to investigate the effects of intermittent hypoxic treatment (IHT) on cognitive functions in a mouse model of AD and unravel the mechanism of action of IHT.MethodsSix-month-old APPswe/PS1dE9 (APP/PS1) male mice were exposed to hypoxic environment (14.3% O2) 4 h/day for 14 days or 28 days. Cognitive functions were measured by Morris water maze test after either 14 days or 42 days of interval. Thereafter the distribution of amyloid plaque and microglial activation were determined by mouse brain immunohistochemistry, while the amyloid beta (Aβ) and inflammatory cytokines were measured by ELISA and Western Blot. Microarray was used for studying gene expressions in the hippocampus.ResultsIHT for 14 days or 28 days significantly improved the spatial memory ability of the 6-month-old APP/PS1 mice. The memory improvement by 14 days IHT lasted to 14 days, but not to 42 days. The level of Aβ plaques and neurofilament accumulations was reduced markedly after the IHT exposure. IHT reduced the pro-inflammatory cytokines IL-1β, IL-6 levels, and β-secretase cleavage of APP processing which implies reduced Aβ production. Microarray analysis revealed a large number of genes in the hippocampus were significantly altered which are known to be metabolism-regulated genes.ConclusionsThis study provides evidence of the beneficial effect of IHT on the progression of AD by alleviating memory impairment, reducing Aβ accumulation and inflammation in the brain. IHT can be developed as a novel measure to relieve the progression of AD by targeting multiple pathways in the AD pathogenesis.

Highlights

  • Alzheimer’s disease (AD) is a progressive, degenerative, and terminal disease without cure

  • We found that intermittent hypoxic treatment (IHT) alleviated the cognitive deficits, and inhibited Amyloid beta (Aβ) production reducing Aβ fibrils in 6-month-old amyloid precursor protein (APP)/PS1 mice, suggesting that IHT is an effective approach for inhibiting the onset of Aβ deposition

  • IHT alleviates cognitive impairment in 6‐month‐old APP/ PS1 mice IHT for 14 days or 28 days Six-month-old APP/PS1 transgenic male mice were subjected to intermittent hypoxia

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Summary

Introduction

Alzheimer’s disease (AD) is a progressive, degenerative, and terminal disease without cure. Yue et al Alzheimer’s Research & Therapy (2021) 13:194 performance by way of adaptation to reduce the oxygen environment [2,3,4]. More and more research evidenced that IHT can be beneficial for the treatment of a wide range of diseases such as chronic heart and lung diseases, hypertension [5], iron-deficiency anemia [6], Parkinson’s disease, and ischemic coronary artery diseases [7,8,9]. IHT has been applied for the treatment and prevention of chronic bronchial diseases (e.g., asthma) as a non-invasive, auxiliary treatment, via initiating a cascade of beneficial adaptive responses without adverse effects [10,11,12,13,14]. The consequences of IHT on the pathological processes of Alzheimer’s disease (AD) are not defined

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