Drosophila Sirtuin 1 plays a neuroprotective role in altering Alzheimer’s disease-related pathologies in flies

Sirtuin, a Class III histone deacetylase enzyme dependent on nicotinamide adenine dinucleotide, plays a pivotal role in aging and age-related diseases. Numerous studies have highlighted the involvement of sirtuins in Alzheimer’s and other neurodegenerative diseases; however, their molecular mechanisms and possible interactions with Alzheimer’s disease (AD)-associated genes remain unclear. In this study, using a Drosophila melanogaster model of AD, we investigated the potential genetic interactions between sirtuin and AD-associated genes, including amyloid-beta 42, Appl, and Tau. Our findings show that the overexpression or downregulation of Drosophila Sirtuin 1 alters AD-related pathologies such as the rough eye phenotype, behavioral impairments, and excessive cell death observed in AD model flies. In addition, the observed rescue of AD pathologies appears to be associated with sirtuin overexpression, which modulates c-Jun N-terminal kinase and Notch signaling pathways in flies. These findings show that Sirtuin1 plays a neuroprotective role in AD.