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

Abstract

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

TGR5 expression was selectively decreased in the medial septal (MS) cholinergic neurons during middle-late AD stages. Bidirectional genetic regulation of TGR5 in MS cholinergic neurons significantly affected cognition and adult hippocampal neurogenesis in mice. Pharmacological activation of TGR5 in the MS not only increased cholinergic neuronal activity and acetylcholine release, but also enhanced DG glutamatergic neuronal activity, acetylcholine levels and neurogenesis in AD mice. TGR5 modulated cognition and neurogenesis via the MS^{cholinergic(ChAT)}→ DG^{glutamatergic(Glu)} 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.