What is it about?

Alzheimer’s disease (AD) is a progressive and terminal brain disorder that primarily affects the elderly population and is currently the seventh leading cause of death worldwide. AD patients suffer from memory loss and cognitive impairment. A significant amount of research is dedicated to understanding why AD patients lose their memory and how we can prevent it. In a healthy brain, neurons are an important type of cell that carry and encode memory information. Additionally, immune cells in the brain, called glia, provide a support system for neurons and maintain the brain free of infection and the accumulation of toxic deposits. In the brains of AD patients, neurons die, and glia become dysfunctional, which leads to the buildup of toxic deposits and memory impairment. Despite many years of extensive research on AD, there are currently no effective drugs that can rescue brain function or stop the disease progression. G protein-coupled receptors (GPCRs) are ubiquitously expressed in the human body and play important roles in physiological and pathological conditions. Medications that activate or block the actions of GPCRs are used to control blood pressure, alleviate pain, and manage neuropsychiatric disorders, amongst other conditions. However, the beneficial effects of many GPCR-targeted medications are usually associated with unwanted side effects. Accordingly, 'biased' GPCR drugs are currently being tested in various therapeutic areas that are potentially more selective and safer therapeutics in the absence of unwanted side effects. In this study, we explored the biological mechanisms of a GPCR called GPR3. GPR3 levels are elevated in a subset of AD patients. Our previous work showed that deletion of the Gpr3 gene in mouse models of AD lowered the levels of toxic deposits, specifically amyloid plaques, in the brains of mice. However, genetic deletion of Gpr3 also leads to elevated anxiety levels and memory impairment. As such, we developed a biased GPR3 mouse model and determined that biased GPR3 activation reduces the amyloid plaque burden in the absence of an effect on anxiety levels and cognitive function. Biased GPR3 activation is also accompanied by activation of the brain’s protective immune response initiated by glia. Thus, these studies indicate that biased GPR3 therapeutics would be potentially neuroprotective and a safer avenue for therapeutic intervention in AD.

Featured Image

Why is it important?

Several GPCRs are implicated in the pathophysiology of AD. However, biased GPCR signaling is a largely unexplored area of investigation in AD. This study provides the first demonstration of the putative therapeutic benefits of biased GPCR activation for the treatment of AD. We show that we can effectively reduce the burden of toxic deposits of amyloid plaques in the absence of detrimental side effects, e.g., elevated anxiety levels. Given that the majority of AD therapeutic intervention strategies have failed to demonstrate clinical efficacy, our findings open a previously unexplored avenue for safer therapeutic intervention for AD, which will hopefully lead to the development of drugs that can successfully halt AD progression.


A tremendous amount of time and resources have been devoted to developing therapeutic intervention strategies for AD that directly target the classic pathological hallmarks of disease progression. The GPCR field is undergoing a renaissance with the discovery of biased ligands in numerous therapeutic areas. Several GPCRs are intricately involved in AD pathogenesis. We show proof of concept that biased GPR3 signaling alleviates AD pathology while sparing the beneficial effects of GPR3 signaling. Thus, I believe that biased GPCR ligands represent a rich and vastly underexplored opportunity to develop safer therapeutics for AD and numerous other disorders that are associated with GPCR dysfunction.

Amantha Thathiah
University of Pittsburgh School of Medicine

Read the Original

This page is a summary of: G protein–biased GPR3 signaling ameliorates amyloid pathology in a preclinical Alzheimer’s disease mouse model, Proceedings of the National Academy of Sciences, September 2022, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2204828119.
You can read the full text:



The following have contributed to this page