Up-regulation of GPR139 in the medial septum ameliorates cognitive impairment in two mouse models of Alzheimer’s disease

•GPR139 activation in the brain ameliorated Aβ1-42-induced cognitive impairment.•GPR139 activation alleviated Aβ1-42-induced apoptosis and synaptotoxicity in the basal forebrain.•GPR139 overexpression in the MS ameliorated cognitive impairment in APP/PS1 mice.•GPR139 overexpression in the MS alleviated apoptosis and synaptotoxicity in APP/PS1 mice. G-protein coupled receptors (GPCRs) constitute the largest class of cell surface receptors and present prominent drug targets. GPR139 is an orphan GPCR detected in the septum of the brain. However, its roles in cognition are still unclear. Here we first established a mouse model of cognitive impairment by a single intracerebroventricular injection of aggregated amyloid-beta peptide 1–42 (Aβ1-42). RNA-sequencing data analysis showed that Aβ1-42 induced a significant decrease of GPR139 mRNA in the basal forebrain. Using GPR139 agonist JNJ-63533054 and behavioral tests, we found that GPR139 activation in the brain ameliorated Aβ1-42-induced cognitive impairment. Using western blot, TUNEL apoptosis and Golgi staining assays, we showed that GPR139 activation alleviated Aβ1-42-induced apoptosis and synaptotoxicity in the basal forebrain rather than prefrontal cortex and hippocampus. The further study identified that GPR139 was widely expressed in cholinergic neurons of the medial septum (MS). Using the overexpression virus and transgenic animal model, we showed that up-regulation of GPR139 in MS cholinergic neurons ameliorated cognitive impairment, apoptosis and synaptotoxicity in APP/PS1 transgenic mice. These findings reveal that GPR139 of MS cholinergic neurons could be a critical node in cognition and potentially provides insight into the pathogenesis of Alzheimer’s disease.