Cholinergic G protein‐coupled bile acid receptor 1 (TGR5/GPBA) in the medial septal orchestrates adult hippocampal neurogenesis and cognition in Alzheimer's disease mice

BACKGROUND AND PURPOSE: The pathological role of the bile acid receptor TGR5/GPBA in Alzheimer's disease (AD) is not fully understood. We investigated the pharmacological effects and mechanisms of TGR5 in AD model mice. EXPERIMENTAL APPROACH: TGR5 expression was assessed in AD mice using immunofluorescence and immunoblotting. Bidirectional modulation of TGR5 expression was achieved via stereotaxic delivery of adeno-associated virus vectors, while localized pharmacological activation was conducted through intracerebral cannula implantation. Cognition was evaluated using the Morris water maze and novel object recognition test. Adult hippocampal neurogenesis was assessed via immunofluorescence. Neuronal activity was analysed using immunofluorescence, fibre photometry and chemogenetics-coupled fibre photometry. Acetylcholine dynamics were monitored using fibre photometry, both alone and in combination with chemogenetic manipulation. KEY RESULTS: circuit. Furthermore, α7 nAChRs in the DG were involved in TGR5-mediated improvements in cognition and neurogenesis. CONCLUSION AND IMPLICATIONS: Our findings demonstrate that TGR5 in MS cholinergic neurons is critical during the middle-late stage of AD and provide valuable insights into the underlying neuronal circuit mechanisms. TGR5 (GPBA) represents a potential therapeutic target for AD treatment.