LAUSR

Significance Levels of the orphan G protein–coupled receptor GPR3 are elevated in a subset of patients with Alzheimer’s disease (AD). Our group previously showed that genetic deletion of Gpr3 attenuates amyloid-β (Aβ) pathology in multiple AD mouse models, highlighting the therapeutic potential of GPR3 as a drug target for AD. However, Gpr3-deficient mice display several adverse phenotypes, including anxiety-like behavior and cognitive deficits. Here, we genetically modified Gpr3 in naive mice and in a preclinical AD mouse model and demonstrated that biased GPR3 signaling reduces AD pathology and induces glial activation in the absence of an effect on basal anxiety levels or cognitive function. Thus, biased GPR3 therapeutics are potentially neuroprotective and a safer avenue for therapeutic intervention in AD.