The deposition of neurotoxic beta-amyloid plaques plays a central role in the pathogenesis of Alzheimer's disease. At the molecular level, the generation of beta-amyloid peptides involves the site-specific cleavage of the precursor protein by beta-site APP cleavage enzyme (BACE) and presenilin. Although acute or chronic sustained hypoxia appears to increase the generation of beta-amyloid peptides via the HIF-1 alpha dependent upregulation of BACE, the effect of chronic intermittent hypoxia (CIH) on the generation of beta-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 beta-amyloid peptides, and the expressions of BACE, presenilin and HIF-1 alpha protein levels, in the hippocampus of CIH rats. Moreover, the CIH-induced hippocampal beta-amyloid peptide generation could be abolished by a daily pharmacological administration of melatonin (10mg/kg), which reduced the BACE but not presenilin expression. Also, there were no significant differences in the hippocampal HIF-1 alpha 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 beta-amyloid peptide generation in the hippocampus, but also pointed out the therapeutic value of melatonin in reducing beta-amyloid peptide generation in patients suffering from chronic obstructive sleep apnea syndrome.
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