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2023 Alzheimer's Association Research Fellowship (AARF)

Biased GPR3 Signaling Modulates Neuronal Function in AD mice and iNs

Could moderating the function of a protein help prevent beta-amyloid in the brain during Alzheimer’s?

Yunhong Huang, Ph.D.
University of Pittsburgh
Pittsburgh, PA - United States


Cells sense their environment in part through the use of specialized proteins, known as receptors, that in turn respond by activating other proteins. One receptor important for Alzheimer’s is G protein-coupled receptor 3 (GPR3). Research by Dr. Yunhong Huang and others show that GPR3 interacts with proteins inside nerve cells to increase production of beta-amyloid, a hallmark protein of Alzheimer’s. To understand ways to overcome this, Dr. Huang’s team has created a genetically engineered Alzheiner’s-like mouse model that has a variation of the GPR3 protein. This variation  of GPR3 does not appear to trigger beta-amyloid production, but still maintains other important functions.

Research Plan

Dr. Huang’s team will now determine where the GPR3 protein variation is located inside nerve cells collected from the genetically-engineered Alzheimer's-like mice, to better understand this receptor’s function and the types of proteins it may interact with. To do this, Dr. Huang’s team will fluorescently label GPR3 to view it under specialized microscopes. The researchers will assess the mice for symptoms of cognitive disease and measure protein levels in their synapses – the specialized structures nerve cells use to send signals to one another and communicate.  Through this work, Dr. Huang will determine whether impairing part of GPR3’s function might protect the mice from cognitive disease.

Dr. Huang’s team will then perform similar experiments using skin cells donated by individuals with and without Alzheimer’s. The researchers will reprogram the skin cells into nerve cells that either make normal GPR3 protein or the GPR3 variation. They will use specialized  microscopes to measure levels of beta-amyloid and synapse proteins in the cells.


Findings from this study could determine whether adjusting the function of GPR3 might be an effective strategy for preventing brain changes associated with Alzheimer’s, including accumulation of beta-amyloid. This could inform studies in humans investigating this novel therapeutic approach.

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