Long-term oral melatonin alleviates memory deficits, reduces amyloid-β deposition associated with downregulation of BACE1 and mitophagy in APP/PS1 transgenic mice.

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 Aβ40 and Aβ42. 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.