Dementia is recorded 7th leading cause of death in 2021 while threatening the quality of life in aging population globally. Alzheimer\'s disease (AD) is the most representative class of dementia which has been characterized multiple pathologic factors including amyloid-β (Aβ) plaques, oxidative stress, neurofibrillary tangle (NFT) and neuronal impairments. Recent studies have been reporting a significant decrease in intracellular pH and high level of neuroinflammation in AD patients’ brains. Based on these findings, many studies have been attempted to develop the novel therapeutic drugs for AD continuously. Melatonin (N-acetyl-5-methoxytryptamine) as the metabolite of tryptophan, synthesizes mainly in the pineal gland, which contributes to various physiological functions. Melatonin has reported antioxidant properties which reduce oxidative stress and inflammation, and it shows neuroprotective effects, promoting neuronal survival and in AD. In this study, we investigated the gene expression through the total RNA-sequencing from an AD model mouse brain and blood. We identified Gpr65 highly upregulated in AD mouse sample which is significantly modulated after melatonin treated in HT22 and primary neuron. Although further studies need to identify molecular mechanisms more confidently, our results suggest that Gpr65 has its potential to be a novel AD-related gene which regulates neuroinflammation by interacting with melatonin.