Melatonin reduces hippocampal beta-amyloid generation in rats exposed to chronic intermittent hypoxia.
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.
Ng
Kwong-Man
KM
Research Centre of Heart, Brain, Hormone and Healthy Ageing, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong. skykmng@hkucc.hku.hk
Lau
Chi-Fai
CF
Fung
Man-Lung
ML
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D053763:Presenilins / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053763:Presenilins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat; D008550:Melatonin