GV1001 modulates neuroinflammation and improves memory and behavior through the activation of gonadotropin-releasing hormone receptors in a triple transgenic Alzheimer’s disease mouse model

•GV1001 improved memory and cognition in both young and old 3xTg-AD mice.•GV1001 reduced the levels of Aβ oligomers and phosphorylated tau.•GV1001 reduced neuroinflammation by shifting phenotype of microglial and astrocyte.•GV1001 bound to gonadotropin-releasing hormone receptors.•Intracellular cAMP level increased after treatment with GV1001. GV1001 protects neural cells from amyloid-β (Aβ) toxicity and other stressors in in vitro studies and demonstrates clinically beneficial effects in patients with moderate to severe Alzheimer’s disease (AD). Here, we investigated the protective effects and mechanism of action of GV1001 in triple transgenic AD (3xTg-AD) mice. We found that GV1001 improved memory and cognition in middle- and old-aged 3xTg-AD mice. Additionally, it reduced Aβ oligomer and phospho-tau (Ser202 and Thr205) levels in the brain, and mitigated neuroinflammation by promoting a neuroprotective microglial and astrocyte phenotype while diminishing the neurotoxic ones. In vitro, GV1001 bound to gonadotropin releasing hormone receptors (GnRHRs) with high affinity. Levels of cyclic adenosine monophosphate, a direct downstream effector of activated GnRHRs, increased after GV1001 treatment. Furthermore, inhibition of GnRHRs blocked GV1001-induced effects. Thus, GV1001 might improve cognitive and memory functions of 3xTg-AD mice by suppressing neuroinflammation and reducing Aβ oligomers levels and phospho-tau by activating GnRHRs and their downstream signaling pathways.