The identification by Thathiah and coworkers of the orphan G protein-coupled receptor 3 (GPR3) as a regulator of amyloid-β production is very interesting. Particularly intriguing is the idea that this protein apparently affects formation and cell-surface localization of γ-secretase to influence processing of APP, but not of Notch. While these observations suggest that GPR3 may be a useful target for development of anti-amyloid therapy for Alzheimer disease (AD), further evaluations are needed to examine its in-vivo impact on amyloid deposition in AD mouse models as well as its functional role(s), including in learning and memory as GPR3 is highly expressed in neurons of the hippocampus. Although Notch signaling may not be influenced by GPR3, the observation that GPR3 knockout mice exhibit premature ovarian aging indicates that other important pathways are regulated by GPR3 and that targeting GPR3 may lead to adverse affects in the brain. Thus, careful examination of GPR3’s therapeutic potential should point us in the right direction regarding development of drugs that selectively...  Read more

The identification by Thathiah and coworkers of the orphan G protein-coupled receptor 3 (GPR3) as a regulator of amyloid-β production is very interesting. Particularly intriguing is the idea that this protein apparently affects formation and cell-surface localization of γ-secretase to influence processing of APP, but not of Notch. While these observations suggest that GPR3 may be a useful target for development of anti-amyloid therapy for Alzheimer disease (AD), further evaluations are needed to examine its in-vivo impact on amyloid deposition in AD mouse models as well as its functional role(s), including in learning and memory as GPR3 is highly expressed in neurons of the hippocampus. Although Notch signaling may not be influenced by GPR3, the observation that GPR3 knockout mice exhibit premature ovarian aging indicates that other important pathways are regulated by GPR3 and that targeting GPR3 may lead to adverse affects in the brain. Thus, careful examination of GPR3’s therapeutic potential should point us in the right direction regarding development of drugs that selectively target GPR3 for AD.

View all comments by Philip Wong

This paper is on the identification of a novel receptor that can regulate Aβ production. The receptor is a GPCR coupled to adenylate cyclase, but its natural ligand is unknown, and cAMP elevation by other means did not alter Aβ production. siRNA knockdown of the GPCR3 lowers Aβ production, but it is unclear whether this means an antagonist would do the same. Other evidence suggests that GPCR3 enhances the formation of mature γ-secretase complexes with increased Aβ production, but no effect on Notch processing. This evidence, along with a previous report that knockout of GPCR3 has only a mild phenotype, without any apparent Notch loss-of-function, suggests this orphan receptor might be a worthy target. In my view, the jury is still out, especially since it is hard to see how facilitating γ-secretase maturation leads to a selective elevation of APP processing over Notch.

View all comments by Michael Wolfe