Diabetes mellitus (DM), one of metabolic diseases, has been suggested as a risk factor for Alzheimer's disease (AD). However, how the metabolic pathway activates amyloid precursor protein (APP) processing enzymes then contributes to the increase of amyloid-beta (Aβ) production, is not clearly understood. In the present study, we aimed to examine the protective effect of melatonin against hyperglycemia-induced alterations in the amyloidogenic pathway. High concentration of glucose was used to induce hyperglycemia in human neuroblastoma SH-SY5Y cells. We found that 30 mM glucose affected the expression of insulin receptors and glucose transporters, which indicated the disruption of glucose sensing. High glucose induced the activation of the phosphorylated protein kinase B (pAkt)/GSK-3β signaling pathway and a significant increase in the expression of β-site beta APP cleaving enzyme (BACE1), presenilin1 (PS1) and Aβ42. Pretreatment with melatonin significantly reversed these parameters. We also showed that these effects are similar to those effects in the presence of the GSK-3β blocker, N-(4-methoxybenyl)-N'-(5-nitro-1,3-thiazol-2-yl) urea (ARA) in glucose-treated hyperglycemic cells. These suggested that melatonin exerted an inhibitory effect on the activation of APP-cleaving enzymes via the GSK-3β signaling pathway. Pretreatment with luzindole, a melatonin receptor MT1 antagonist, significantly prevented the effect of melatonin on the glucose-induced increase level of APP processing enzymes. This suggested that melatonin attenuated the toxic effect on hyperglycemia involving the amyloidogenic pathway partially mediated via melatonin receptor. Taken together the present results suggested that melatonin has a beneficial role in preventing Aβ generation in a cellular model of hyperglycemia-induced DM.
Keywords: Alzheimer’s disease; Amyloid-beta; Diabetes mellitus; High glucose; Hyperglycemia; Melatonin receptor.
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.