| Introduction Alzheimer's disease (AD) patients frequently show a disturbed circadian rhythm. Decreased melatonin levels and the degenerative changes in the suprachiasmatic nucleus (SCN) are considered to be the basis of this biological rhythm disorder. Our previous studies have shown that cerebrospinal fluid (CSF) melatonin levels are dramatically decreased in AD, moreover the decreased CSF melatonin level is negatively correlated with the Braak stages, which are the most clinically relevant staging of Alzheimer's neuropathological changes. Recently, melatonin was found to have neuroprotective actions. We proposed that decreased melatonin might be involved in the early process of AD.Objective In present study, we aimed to investigate the mechanism of the alteration in melatonin synthesis and regulation pathways in AD, hopefully, to clarify the early pathogenesis of AD and to provide evidence for early diagnosis and potential treatment for AD.Methods Postmortem human pineal glands were obtained at autopsy, generally between 1-24h after death and kept frozen at -80℃. Neuropathological diagnosis: 24 cases of definite severe AD(SAD) (Braak VI) (mean age=72.5±2.1 year); 31 cases with mild AD neuropathological changes (MAD) (Braak I - II ) (mean age=73.6±1.6 year); 15 aged controls without AD neuropathological changes (non-AD: NAD) (Braak 0) (mean age=68.2±2.3 year); The CSF from 37 subjects in above three groups were collected and kept -80℃ till assay. The melatonin levels in the pineal extract and in CSF were measured with radioimmunoassy (RIA). Other major monoamine compounds in the synthesis pathway of melatonin (TRP, 5-HT, 5-HIAA, NAS, NE, MIIPG), and in dopamine system (DA, HVA), were measured with high performance liquid chromatography (HPLC). The total protein content of pineal gland was determined with Bradford Protein Assay.Statistics Differences in monoamine levels between groups were tested using the Mann-Whitney U-test. The differences in monoamine levels among three groups were tested by Kruskal-Wallis H-test. Correlations were analyzed by the Spearman correlation test.Results There was no significant difference of the pineal weight among NAD (197.5±16.3 mg), MAD (238.5 ± 19.2 mg) and SAD (227.3 ± 23.ling) (p=0.62) . There was no significant difference of the pineal total protein content among NAD (0.097 ± 0.011 mg/mg tissue ), MAD (0.094 ± 0.009 mg/mg tissue) and SAD (0.118 ± 0.015 mg/mg tissue) (p=0.215) . There was no significant difference in the pineal 5-HT, NAS levels among these three groups (p=0.542 , p=OA35 respectively). A high positive correlation was observed between melatonin levels in pineal gland and in CSF (r=0.68, p<0.0001). The diurnal variation ofpineal melatonin was maintained in NAD, melatonin level during the night was 4 times higher than during the day (77=0.045). But this diurnal variation disappeared in MAD (77=0.089), and even more so in SAD (p=0.331). The night-time pineal melatonin levels were lower in SAD (35.15±16.8 pg/mg tissue) than in NAD (219.23 ± 108.27 pg/mg tissue) (77=0.010) and in MAD (64.03±15.95 pg/mg tissue) (p=0.018). The night-time pineal melatonin/NAS (represents the activity of melatonin synthesis pathway) was lower in SAD (2.97 ± 2.47) than in NAD (16.70± 7.89) (77=0.022) and in MAD (4.55 ± 3.31) (77=0.034). The pineal 5-I1IAA levels were dramatically higher in SAD (2425.75 ± 481.30 pg/mg tissue) than in NAD (667.66± 1 53.30 pg/mg tissue) (p=0.003) and in MAD (1315.35 ± 276.73 pg/mg tissue) (p=0.044). The pineal 5-HIAA/5-HT in SAD (0.27±0.045) and MAD (0.19 ± 0.03) were dramatically higher than that in NAD (0.10 ± 0.022) (p=0.004, p=0.034, respectively) . There was no significant difference of pineal NE and MIIPG/NE among these three groups (p=0.738, p=0.156) . There was no significant difference of pineal DA, HVA, IIVA/DA in DA system among these three groups (p=0.962, p=0.535, p=0.697, respectively).Conclusion (1)The disappearance of melatonin diurnal variation is an early event of AD; (2)The CSF mela...
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