GPR139-mediated cholinergic circuit from the medial septum to the ventral hippocampal CA3 modulates cognitive impairment in Alzheimer's disease.

G-protein coupled receptor 139 (GPR139) has been detected in the medial septum (MS) cholinergic neuron, but its roles in cholinergic circuits associated with Alzheimer's disease (AD) remain unclear. Using a variety of experimental approaches, including the establishment of AD mouse models, viral injection, immunohistochemistry, ELISA, TUNEL apoptosis assay, Golgi staining, electrophysiological recording, fiber photometry, and behavioral tests, we found that knockdown of GPR139 in MS cholinergic neurons exacerbated early-stage cognitive decline, apoptosis, and synaptotoxicity in the basal forebrain of 6-month-old APP/PS1 mice. GPR139 activation by agonist improved memory and increased the firing and excitability of MS cholinergic neurons in ICV-Aβ1-42 mice. Strikingly, the MS provides extensive cholinergic projections to the ventral hippocampal CA3 (vCA3) subregion. Using chemogenetic approaches and 6-/9-month-old APP/PS1 mice, we further showed that inhibiting the MS→vCA3 cholinergic projection disrupted spatial temporal order memory in the early stages of AD, and activation of GPR139 improved memory deficits possibly via the MS→vCA3 cholinergic circuit in the advanced stages. These findings reveal that GPR139 in the MS→vCA3 cholinergic circuit may serve as a critical regulator of cognitive function and offer promising therapeutic strategies for AD.