Search

Melatonin is a tryptophan metabolite synthesized by the pineal gland. Recent research showed that melatonin has a protective effect in Alzheimer's disease (AD). However, its exact mechanism is still unclear. This study was designed to investigate the effects of long-term oral melatonin on spatial learning and memory, Aβ deposition and soluble Aβ levels, amyloidogenic amyloid precursor protein (APP) processing, mitochondrial structure and mitophagy in APP/PS1 transgenic mice, a model of AD. The spatial learning and memory ability of mice were examined by using the Morris water maze. Thioflavin S staining was used to observe Aβ deposition. ELISA was used to evaluate the levels of Aβ 40 and Aβ 42 . The expression levels of mitophagy proteins (PINK1, Parkin, LC3-II and LC3-I) and amyloidogenic APP processing proteins (BACE1, APP and CTFβ) were examined by western blotting analysis. Finally, transmission electron microscopy was used to observe mitochondrial structure and mitophagy vesicles. Our results showed that APP/PS1 transgenic mice with long-term oral melatonin showed improved spatial learning, alleviated memory impairment, reduced Aβ deposition and restrained damage of mitochondrial structure. In addition, the number of mitophagy vesicles and expression levels of mitophagy factors (PINK1, Parkin, LC3-II/LC3-I) were decreased, as was the expression levels of amyloidogenic APP processing proteins (BACE1, APP and CTFβ). Long-term oral melatonin decreased Aβ deposition and improved spatial learning and memory in APP/PS1 transgenic mice by a mechanism associated with down-regulation of BACE1 and mitophagy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a progressive neurodegenerative disease which is characterized by the accumulation of amyloid-β peptide (Aβ). Orexin-A is a neuropeptide which has been reported to participate in the pathogenesis of AD. Thus, we aimed to investigate the possible mechanism by which Orexin-A acts in AD. APP/PS1 transgenic mice, an animal model of AD, were intracerebroventricularly injected with Orexin-A. Aβ-treated SH-SY5Y cells were used as a cell model of AD and treated with Orexin-A. The Morris water maze test, fluorescence microscopy, enzyme-linked immunosorbent assay (ELISA), electron microscopy, real-time PCR, and other biochemical assays were conducted. The Morris water maze test showed that Orexin-A aggravated cognitive deficit in APP/PS1 mice. Using thioflavine-S staining and ELISA, we found that Orexin-A promoted Aβ accumulation in APP/PS1 mice. By evaluating mitochondrial morphology, cytochrome c oxidase activity, ATP level, mitochondrial DNA copy number, and reactive oxygen species, we found that Orexin-A aggravated mitochondrial impairment in APP/PS1 mice and Aβ-treated SH-SY5Y cells. Our results indicate that Orexin-A exacerbates AD by inducing mitochondrial impairment. This is a new mechanism that explains how Orexin-A participates in the pathogenesis of AD., (Copyright © 2020 Elsevier B.V. All rights reserved.)