Improved memory learning behavior in AD mice following 21‐day intermittent hypoxia training

Abstract Background The intensity and cumulative dose of intermittent hypoxia (IH) exposures are critical determinants of beneficial vs detrimental effects on the brain. This study tested if moderate, low‐dose IH training (IHT) is safe and effective to improve memory‐learning behavior and to augment neuroprotective trophic/growth factors in mice with transgenic Alzheimer’s disease (AD) traits. Method Twenty‐four triple‐transgenic (JAX MMRRC Stock# 034830) and wild‐type (WT) 12‐month‐old female mice were assigned to 4 groups: WT (n = 8), AD (n = 6), AD+IHT (n = 6), and AD+sham‐IHT (n = 6). Cerebrocortical and hippocampal amyloid‐β (Aβ) 40 and 42 were determined by ELISA. Cerebrocortical contents of brain‐derived neurotrophic factor (BDNF) and erythropoietin (EPO) were quantified by immunoblotting and ELISA. Memory‐learning behavior was tested using Morris water maze (MWM). IHT was conducted between 9AM‐12:00 by exposing AD+IHT mice to alternating 10% O 2 for 6‐min and room‐air for 4‐min, for 10 cycles daily for 21 consecutive days. AD+sham‐IHT group was exposed to room‐air. These protocols were IACUC‐approved. Two‐factor ANOVA was applied to test the significance of age‐factor (12‐ vs ∼13‐month‐old) and IHT‐factor. Tukey’s post hoc analysis was applied if a factor showed significance at P<0.05. The table presents group mean values ±SD. Result Baseline body‐weight and swimming time and distance to find the submerged platform were not different between AD+IHT vs . AD+sham‐IHT, or between WT vs . AD. Cerebrocortical and hippocampal Aβ42 contents were lower (P<0.01) in WT than in AD (table). However, neither age‐factor nor IHT‐factor significantly modified Aβ40 or Aβ42. Cerebrocortical BDNF and EPO tended to be increased following 21‐day IHT. In the AD+IHT mice, overall swimming distance decreased by 1.60±4.36m and distance swum in the opposite quadrant decreased by 0.85±1.13m after 21‐day IHT, but in the AD+sham‐IHT mice, these distances increased by 5.78±6.38m (P=0.041 vs . AD+IHT) and by 0.99±1.35m (P=0.028 vs . AD+IHT). The changes in body weight did not differ between AD+IHT (‐2.3±0.8g) and AD+sham‐IHT (‐1.1±1.0g). Conclusion Moderate low‐dose normobaric IHT is potentially beneficial for enhancing memory‐learning behavior and expressions of cerebrocortical BDNF and EPO contents in AD mice.