Intermittent Hypoxia Training Prevents Deficient Learning-Memory Behavior in Mice Modeling Alzheimer's Disease: A Pilot Study

Myoung-Gwi Ryou; Xiaoan Chen; Ming Cai; Hong Wang; Marianna E Jung; Daniel B Metzger; Robert T Mallet; Xiangrong Shi

doi:10.3389/fnagi.2021.674688

Intermittent Hypoxia Training Prevents Deficient Learning-Memory Behavior in Mice Modeling Alzheimer's Disease: A Pilot Study

Front Aging Neurosci. 2021 Jul 1:13:674688. doi: 10.3389/fnagi.2021.674688. eCollection 2021.

Authors

Myoung-Gwi Ryou¹, Xiaoan Chen^{2

3}, Ming Cai^{2

4}, Hong Wang^{2

4}, Marianna E Jung², Daniel B Metzger², Robert T Mallet⁵, Xiangrong Shi²

Affiliations

¹ Department of Medical Laboratory Science and Public Health, Tarleton State University, Texas A&M University System, Stephenville, TX, United States.
² Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States.
³ College of Sports Science, Jishou University, Jishou, China.
⁴ College of Rehabilitation Sciences, Shanghai University of Medicine and Health Sciences, Shanghai, China.
⁵ Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX, United States.

Abstract

In mouse models of Alzheimer's disease (AD), normobaric intermittent hypoxia training (IHT) can preserve neurobehavioral function when applied before deficits develop, but IHT's effectiveness after onset of amyloid-β (Aβ) accumulation is unclear. This study tested the hypothesis that IHT improves learning-memory behavior, diminishes Aβ accumulation in cerebral cortex and hippocampus, and enhances cerebrocortical contents of the neuroprotective trophic factors erythropoietin and brain-derived neurotrophic factor (BDNF) in mice manifesting AD traits. Twelve-month-old female 3xTg-AD mice were assigned to untreated 3xTg-AD (n = 6), AD+IHT (n = 6), and AD+sham-IHT (n = 6) groups; 8 untreated wild-type (WT) mice also were studied. AD+IHT mice alternately breathed 10% O₂ for 6 min and room air for 4 min, 10 cycles/day for 21 days; AD+sham-IHT mice breathed room air. Spatial learning-memory was assessed by Morris water maze. Cerebrocortical and hippocampal Aβ₄₀ and Aβ₄₂ contents were determined by ELISA, and cerebrocortical erythropoietin and BDNF were analyzed by immunoblotting and ELISA. The significance of time (12 vs. 12 months + 21 days) and treatment (IHT vs. sham-IHT) was evaluated by two-factor ANOVA. The change in swimming distance to find the water maze platform after 21 d IHT (-1.6 ± 1.8 m) differed from that after sham-IHT (+5.8 ± 2.6 m). Cerebrocortical and hippocampal Aβ₄₂ contents were greater in 3xTg-AD than WT mice, but neither time nor treatment significantly affected Aβ₄₀ or Aβ₄₂ contents in the 3xTg-AD mice. Cerebrocortical erythropoietin and BDNF contents increased appreciably after IHT as compared to untreated 3xTg-AD and AD+sham-IHT mice. In conclusion, moderate, normobaric IHT prevented spatial learning-memory decline and restored cerebrocortical erythropoietin and BDNF contents despite ongoing Aβ accumulation in 3xTg-AD mice.

Keywords: Alzheimer's disease; BDNF; beta-amyloid; cerebral cortex; erythropoietin; intermittent hypoxia; memory-learning behavior.