Melatonin regulates the transcription of βAPP‐cleaving secretases mediated through melatonin receptors in human neuroblastoma SH‐SY5Y cells

Abstract

Melatonin is involved in the control of various physiological functions, such as sleep, cell growth and free radical scavenging. The ability of melatonin to behave as an antioxidant, together with the fact that the Alzheimer-related amyloid β-peptide (Aβ) triggers oxidative stress through hydroxyl radical-induced cell death, suggests that melatonin could reduce Alzheimer's pathology. Although the exact etiology of Alzheimer's disease (AD) remains to be established, excess Aβ is believed to be the primary contributor to the dysfunction and degeneration of neurons that occurs in AD. Aβ peptides are produced via the sequential cleavage of β-secretase β-site APP-cleaving enzyme 1 (BACE1) and γ-secretase (PS1/PS2), while α-secretase (ADAM10) prevents the production of Aβ peptides. We hypothesized that melatonin could inhibit BACE1 and PS1/PS2 and enhance ADAM10 expression. Using the human neuronal SH-SY5Y cell line, we found that melatonin inhibited BACE1 and PS1 and activated ADAM10 mRNA level and protein expression in a concentration-dependent manner and mediated via melatonin G protein-coupled receptors. Melatonin inhibits BACE1 and PS1 protein expressions through the attenuation of nuclear factor-κB phosphorylation (pNF-κB). Moreover, melatonin reduced BACE1 promoter transactivation and consequently downregulated β-secretase catalytic activity. The present data show that melatonin is not only a potential regulator of β/γ-secretase but also an activator of α-secretase expression through the activation of protein kinase C, thereby favoring the nonamyloidogenic pathway over the amyloidogenic pathway. Altogether, our findings suggest that melatonin may be a potential therapeutic agent for reducing the risk of AD in humans.

Melatonin ameliorates Aβ42‐induced alteration of βAPP‐processing secretases via the melatonin receptor through the Pin1/GSK3β/NF‐κB pathway in SH‐SY5Y cells

“…Our previous studies showed that melatonin stimulated nonamyloidogenic processing of βAPP by enhancing the expression of ADAM10 and downregulated the amyloidogenic processing secretases BACE1 and PS1 . To investigate the protective effects of melatonin in pathogenic neurotoxic conditions induced by Aβ 42 treatments, cells were pretreated with various concentrations of melatonin (0.01, 0.1, and 1 μmol/L) 1 hour prior to Aβ 42 (1 μmol/L) treatment.…”

“…The therapeutic benefits of melatonin in MCI and AD patients, animal, and aging models along with the restoration of memory deficits have been substantially documented. Our previous studies delineated novel mechanisms of melatonin regulation of βAPP‐processing secretases under physiological conditions . However, to unveil the underlying molecular mechanisms of melatonin regulation under pathological conditions requires further exploration.…”

Effects of the drug combination memantine and melatonin on impaired memory and brain neuronal deficits in an amyloid-predominant mouse model of Alzheimer's disease

“…Furthermore, it was reported that melatonin is able to interact with Aβ‐40 and Aβ‐42 and reduce neuronal damage by inhibiting the progressive formation of β‐sheets and amyloid fibrils in vitro . By regulating several crucial protein kinases including nuclear factor‐κB kinase (pNF‐κB), cyclin‐dependent kinase 5 (cdk5) and activated glycogen synthase kinase‐3β(GSK‐3β), melatonin attenuates hyperphosphorylation of tau and decreases Aβ accumulation …”

Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

“…It has been reported that melatonin elevates ADAM10 level in HEK293 and neuronal SH-SY5Y cells via G protein-coupled receptor-induced PKC/Erk activation (Panmanee et al, 2015; Shukla et al, 2015). This effect seems to depend on human ADAM10 promoter region −1193 to −555 as a respective deletion construct failed to respond in a reporter gene assay (Shukla et al, 2015).…”

“…Finally, as melatonin seems to be able to increase the level of deacetylase in young and aged primary neurons (Tajes et al, 2009), the observed induction of ADAM10 by melatonin (Panmanee et al, 2015; Shukla et al, 2015) might also rely on deacetylase activation.…”