G protein‐biased GPR3 signaling induces glial activation and ameliorates amyloid pathology in a preclinical Alzheimer’s disease mouse model

Background Biased G protein-coupled receptor (GPCR) ligands preferentially activate protein- or β-arrestin signaling pathways and are leading to the development of drugs with superior efficacy reduced side-effects in heart disease, pain management, neuropsychiatric disorders. Although GPCRs implicated pathophysiology Alzheimer’s disease (AD), biased GPCR is an unexplored area investigation AD. Previous work demonstrated that Gpr3 deficiency ameliorates amyloid-β (Aβ) pathology. However, Gpr3-deficient mice display several adverse phenotypes, including elevated anxiety-like behavior, fertility, memory impairment, which potentially associated impaired protein-signaling. We hypothesized generation a protein-biased GPR3 mouse model, maintains protein-signaling while eliminating signaling, would attenuate AD-associated phenotypes preserving beneficial effects GPR3-mediated Methods used CRISPR/Cas9 genome-editing strategy develop two novel models. utilized broad range molecular, cellular, biochemical methodologies, mass spectrometry, immunoblot immunohistochemical analyses, RNA profiling, behavioral testing determine physiological relevance naïve preclinical AppNL-G-F AD model. Results that, contrast mice, do not anxiety levels, cognitive impairment. then established expressed neurons, microglia, astrocytes cell-type-specific on pathogenesis. Accordingly, we leads reduction Aβ activation hypertrophy disease-associated-microglia (DAM) pan-reactive astrocytes, increase amyloid plaque compaction mice. Conclusions These studies provide first demonstration neuronal regulation microglial astrocytic neuroinflammation model open exciting agonism as therapeutic intervention for