Melatonin reduces hippocampal β-amyloid generation in rats exposed to chronic intermittent hypoxia

The deposition of neurotoxic β-amyloid plaques plays a central role in the pathogenesis of Alzheimer's disease. At the molecular level, the generation of β-amyloid peptides involves the site-specific cleavage of the precursor protein by β-site APP cleavage enzyme (BACE) and presenilin. Although acute or chronic sustained hypoxia appears to increase the generation of β-amyloid peptides via the HIF-1α dependent upregulation of BACE, the effect of chronic intermittent hypoxia (CIH) on the generation of β-amyloid peptides remains uncertain. In this study, we have evaluated such contention in the rat hippocampus, and we found that short-term CIH exposure (3 days) caused significant increases in the generation of β-amyloid peptides, and the expressions of BACE, presenilin and HIF-1α protein levels, in the hippocampus of CIH rats. Moreover, the CIH-induced hippocampal β-amyloid peptide generation could be abolished by a daily pharmacological administration of melatonin (10 mg/kg), which reduced the BACE but not presenilin expression. Also, there were no significant differences in the hippocampal HIF-1α protein levels between the melatonin- and vehicle-treated CIH groups. Our study not only provided the first evidence that short-term CIH exposure could induce the β-amyloid peptide generation in the hippocampus, but also pointed out the therapeutic value of melatonin in reducing β-amyloid peptide generation in patients suffering from chronic obstructive sleep apnea syndrome.