Evaluating Potential of Estrogen and Melatonin in Alzheimer’s Disease: Evidence from Cell and Fly Models

Alzheimer’s Disease (AD), an age-related neuroimmune disorder that is the seventh leading cause of death in the United States, has risk factors of reduced postmenopausal estrogen and the APOE4 allele, which causes inefficient lipid transport. Biomarkers of β-amyloid (Aβ) buildup, reduced nitric oxide (NO), increased caspase-3, and lipid droplet (LD) accumulation arise. Current drugs target symptoms temporarily and cause side effects like cognitive decline. Estrogen and melatonin, both able to cross the blood-brain barrier, offer potential as natural treatments. Estrogen degrades Aβ and inhibits caspase-3; melatonin reduces Aβ aggregates and neuroinflammation. We hypothesized that estrogen and melatonin could reduce LDs, prevent cell death via NO pathways, lower caspase-3 levels, and improve movement in Aβ-transgenic Drosophila melanogaster. Molecular docking analyzed their interactions with key AD proteins. In vitro assays on Aβ-treated human cell lines as AD models evaluated their effects. In vivo tests assessed motor function in Aβ-mutant flies. Estrogen and melatonin have high binding affinity with AD proteins including Aβ, confirming interaction with proteins. They had the same protein binding sites, suggesting synergy. They statistically significantly (p < 0.05) reduced LDs and caspase-3 levels in HTB-11 cells and improved cell proliferation under Aβ conditions, with diminished effects under inhibited NO synthase. Treated Aβ flies displayed improved mobility compared to untreated ones. These findings support the hypothesis that estrogen and melatonin have protective effects against AD in vitro and in vivo. They reduce LD buildup and enhance NO production, highlighting their potential as natural treatments in conjunction with other AD treatments.