Melatonin is involved in the physiological regulation of the β‐amyloid precursor protein (βAPP)‐cleaving secretases which are responsible for generation of the neurotoxic amyloid beta (Aβ) peptide, one of the hallmarks of Alzheimer's disease (AD) pathology. In this study, we aimed to determine the underlying mechanisms of this regulation under pathological conditions. We establish that melatonin prevents Aβ₄₂‐induced downregulation of a disintegrin and metalloproteinase domain‐containing protein 10 (ADAM10) as well as upregulation of β‐site APP‐cleaving enzyme 1 (BACE1) and presenilin 1 (PS1) in SH‐SY5Y cell cultures. We also demonstrate that the intrinsic mechanisms of the observed effects occurred via regulation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and glycogen synthase kinase (GSK)‐3β as melatonin reversed Aβ₄₂‐induced upregulation and nuclear translocation of NF‐κBp65 as well as activation of GSK3β via its receptor activation. Furthermore, specific blocking of the NF‐κB and GSK3β pathways partially abrogated the Aβ₄₂‐induced reduction in the BACE1 and PS1 levels. In addition, GSK3β blockage affected α‐secretase cleavage and modulated nuclear translocation of NF‐κB. Importantly, our study for the first time shows that peptidyl‐prolyl cis‐trans isomerase NIMA‐interacting 1 (Pin1) is a crucial target of melatonin. The compromised levels and/or genetic variation of Pin1 are associated with age‐dependent tau and Aβ pathologies and neuronal degeneration. Interestingly, melatonin alleviated the Aβ₄₂‐induced reduction of nuclear Pin1 levels and preserved the functional integrity of this isomerase. Our findings illustrate that melatonin attenuates Aβ₄₂‐induced alterations of βAPP‐cleaving secretases possibly via the Pin1/GSK3β/NF‐κB pathway.

中文翻译：

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褪黑素通过SH1 / SY5Y细胞中的Pin1 /GSK3β/NF-κB途径通过褪黑激素受体改善了Aβ42诱导的βAPP加工分泌酶的改变。

褪黑素参与了对β淀粉样前体蛋白（βAPP）切割分泌酶的生理调节，这些酶负责产生神经毒性淀粉样β（Aβ）肽，这是阿尔茨海默氏病（AD）病理特征之一。在这项研究中，我们旨在确定病理条件下该调控的潜在机制。我们确定褪黑激素可预防_Aβ42在SH‐SY5Y细胞培养物中诱导的含整合素和金属蛋白酶结构域蛋白10（ADAM10）的下调以及β位APP裂解酶1（BACE1）和早老素1（PS1）的上调。我们还证明了观察到的效应的内在机制是通过调节激活的B细胞核因子κ轻链增强剂（NF-κB）和糖原合酶激酶（GSK）-3β来实现的，因为褪黑激素逆转了_Aβ42诱导的上调NF-κBp65的核转位以及GSK3β的受体活化。此外，对NF-κB和GSK3β途径的特异性阻断部分废除了_Aβ42导致BACE1和PS1水平降低。此外，GSK3β阻滞影响α-分泌酶的裂解并调节NF-κB的核易位。重要的是，我们的研究首次表明，肽基脯氨酰顺反异构酶NIMA-interacting 1（Pin1）是褪黑激素的重要靶标。Pin1的受损水平和/或遗传变异与年龄相关的tau和Aβ病理以及神经元变性有关。有趣的是，褪黑素减轻了_Aβ42诱导的核Pin1水平的降低，并保留了这种异构酶的功能完整性。我们的发现表明，褪黑素可能通过Pin1 /GSK3β/NF-κB途径减弱_Aβ42诱导的βAPP裂解分泌酶的改变。