Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types

Melatonin is released in mammals during the dark phase of the circadian cyc le, and its production declines with age in animals and humans. Since suppl emental administration of melatonin may be beneficial in delaying age-relat ed degenerative conditions, it is necessary to study its effect on neuronal differentiation and the processing of key neuronal proteins, such as beta- amyloid precursor protein (beta APP) and synaptophysin. One of the importan t pathological hallmarks of Alzheimer's disease (AD) is the cerebrovascular deposition of amyloid plaques. The amyloid in senile plaques is mainly com posed of the amyloid beta-peptide (A beta) of 39-43 amino acids derived fro m a larger beta APP. The proteolytic cleavage by 'alpha-secretase' generate soluble derivatives of beta APP (sAPP), lacking the cytoplasmic tail, tran smembrane domain, and a small portion of the extracellular domain. Here lev els of sAPP and beta APP were analyzed in cell lines of different origins b y Western immunoblot of samples from conditioned media and cell lysates, re spectively. Normal levels of secretion of sAPP into conditioned media were severely inhibited by treating different cell lines with a high dose of mel atonin. In PC12 cells, levels of the fully matured beta APP forms of the po st-Golgi compartment were more drastically decreased than the unglycosylate d beta APP of the endoplasmic-reticulum (ER) forms. In other cell types, th e unglycosylated ER-bound beta APP derivatives are predominant forms that w ere marginally affected by melatonin treatment. When the treatment of cells with melatonin was withdrawn, the normal level of secretion of sAPP was re stored. Melatonin reduces the secretion of soluble A beta. Melatonin also i nhibits the secretion of synaptophysin in PC12 cells. Taken together, these data suggest that melatonin probably affects the secretion of sAPP in the conditioned medium by interfering with its full maturation, and melatonin a lso affects the presysnaptic terminal marker.