Melatonin ameliorates Aβ 42 42 ‐induced alteration of β APP APP ‐processing secretases via the melatonin receptor through the Pin1/ GSK GSK 3β/ NF NF ‐κB pathway in SH SH ‐ SY SY 5Y cells

摘要

Abstract Melatonin is involved in the physiological regulation of the β‐amyloid precursor protein (β APP )‐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 Aβ 42 ‐induced downregulation of a disintegrin and metalloproteinase domain‐containing protein 10 ( ADAM 10) as well as upregulation of β‐site APP ‐cleaving enzyme 1 ( BACE 1) and presenilin 1 ( PS 1) in SH ‐ SY 5Y 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 Aβ 42 ‐induced upregulation and nuclear translocation of NF‐κBp65 as well as activation of GSK 3β via its receptor activation. Furthermore, specific blocking of the NF ‐κB and GSK 3β pathways partially abrogated the Aβ 42 ‐induced reduction in the BACE 1 and PS 1 levels. In addition, GSK 3β 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 Aβ 42 ‐induced reduction of nuclear Pin1 levels and preserved the functional integrity of this isomerase. Our findings illustrate that melatonin attenuates Aβ 42 ‐induced alterations of β APP ‐cleaving secretases possibly via the Pin1/ GSK 3β/ NF ‐κB pathway.