Targeting Adhesion G Protein-Coupled Receptor GPR56 in Alzheimer’s Disease

The proposed project aims to investigate how microglial GPR56 affects the progression of Alzheimer’s disease by using novel mouse models and cutting-edge single-cell transcriptomic approaches.

The proposed project hypothesizes that microglial GPR56 maintains normal brain homeostasis and prevents the progression of AD pathology. I will test the hypothesis by carrying out: Aim 1 is to explore the function of microglial GPR56 in AD. I will conduct histology and protein analysis and behavior tests on the novel mouse model created by crossing the AD mouse model with microglial GPR56 conditioned knockout mice. Aim 2 is to define the transcriptomic signature of neurons, microglia, and other glial cells in the novel mouse model by single-nucleus RNA-Seq and spatial transcriptomics.

This proposed study provides a novel therapeutic target for Alzheimer’s disease by investigating the role of the adhesion GPCR in microglia. As the second-largest family of GPCRs, adhesion GPCR regulates various developmental and disease processes, but its function in neurodegeneration remains largely unknown. This project highlights the glia-glia communication and neuroinflammation mediated by adhesion GPCR, revealing a potential brand-new signaling pathway and expanding the novel drug development in Alzheimer’s disease.

This proposed study investigates how microglial GPR56 regulates microglia-astrocyte communication and neuroinflammation in Alzheimer’s disease mouse model. The success of this study will further extend our understanding of the glial cells’ functions in the disease progression on both molecular and behavioral aspects. These approaches combined will reveal the glial response on amyloid plaques and the signaling pathways mediated by microglial GPR56, advancing both the field of adhesion GPCR and providing novel therapeutic strategies for Alzheimer’s disease.