Alzheimer’s disease (AD) is the most common neurodegenerative disease mainly caused by abnormal tau phosphorylation, amyloid β (Aβ) deposition and neuroinflammation. As an important environmental factor, hypoxia has been reported to aggravate AD via exacerbating Aβ and tau pathologies. However, the link between hypoxia and neuroinflammation, especially the changes of pro-inflammatory M1 or anti-inflammation M2 microglia phenotypes in AD, is still far from being clearly investigated. Here, we evaluated the activation of microglia in the brains of APPswe/PS1dE9 transgenic (Tg) mice and their wild type (Wt) littermates, after a single episode of acute hypoxia (24 h) exposure. We found that acute hypoxia activated M1 microglia in both Tg and Wt mice as evidenced by the elevated M1 markers including cluster of differentiation 86 (CD86), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-C motif chemokine ligand 2 (CCL2) and CCL3. In addition, the markers of M2 microglia phenotype (arginase-1 (Arg-1), CD206, IL-4 and IL-10) were decreased after acute hypoxia exposure, suggesting an attenuated M2 phenotype of microglia. Moreover, the activation of microglia and the release of cytokines and chemokines were associated with Nuclear factor-κB (NF-κB) induction through toll-like receptor 4 (TLR4). In summary, our findings revealed that acute hypoxia modulated microglia M1/M2 subgroup profile, indicating the pathological role of hypoxia in the neuroinflammation of AD.

Short QT syndrome (SQTS) predisposes afflicted patients to sudden cardiac death. Until now, only one drug—quinidine—has been shown to be effective in patients with SQTS type 1(SQTS1). The objective of this study was to use human‐induced pluripotent stem cell–derived cardiomyocytes (hiPSC‐CMs) from a patient with SQTS1 to search for potentially effective drugs for the treatment of SQTS1 patients. Patch clamp and single‐cell contraction measurements were employed to assess drug effects. Ivabradine, mexiletine, and ajmaline but not flecainide, ranolazine, or amiodarone prolonged the action potential duration (APD) in hiPSC‐CMs from an SQTS1 patient. Ivabradine, ajmaline, and mexiletine inhibited KCNH2 channel currents significantly, which may underlie their APD‐prolonging effects. Under proarrhythmic epinephrine stimulation in spontaneously beating SQTS1 hiPSC‐CMs, ivabradine, mexiletine, and ajmaline but not flecainide reduced the epinephrine‐induced arrhythmic events. The results demonstrate that ivabradine, ajmaline, and mexiletine may be candidate drugs for preventing tachyarrhythmias in SQTS1 patients.

ObjectiveThe present work aims to evaluate the significance of sleep disturbance and electroencephalogram (EEG) alteration in the early stage of Alzheimer's disease (AD).Background and RationaleSleep disturbance is common in patients with AD. It is not known if it can occur at the early stage of AD and if EEG recording may help identify the early sign of the disease.Historical EvolutionSleep disturbance in AD has generally been considered as late consequence of the neurodegenerative process. A growing body of evidence has suggested that the sleep disturbance may occur at the early stage of AD.Updated HypothesisBased on the previous epidemiologic studies and our recent findings, we propose that sleep disturbance may play an important role in the development of AD. Sleep EEG changes may serve as a valuable early sign for AD in the prepathological stage.Early Experimental DataOur data suggested that AβPPswe/PS1ΔE9 transgenic AD mice at preplaque stage (3 and 4 months of age) exhibited different profile of sleep architecture and sleep EEG, which preceded the cognitive deficit and AD neuropathology.Future Experiments and Validation StudiesFuture experiments should focus on sleep EEG changes in patients with mild cognitive impairment and early stage of AD. Follow‐up studies in high‐risk population of the elderly are equally important. In addition, the exact molecular mechanism underlying the sleep disturbance should be thoroughly investigated.Major Challenges for the HypothesisStudies on human participants with early stage of AD, especially the follow‐up studies on the presymptomatic elderly in a large population, are difficult and time‐consuming.Linkage to Other Major TheoriesOur hypothesis may link previous theories to establish a bidirectional relationship between sleep disorders and AD, which may finally form a new schematic mechanism to understand the disease pathogenesis and disease progression.