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Huang Y, Skwarek-Maruszewska A, Horré K, Vandewyer E, Wolfs L, Snellinx A, Saito T, Radaelli E, Corthout N, Colombelli J, Lo AC, Van Aerschot L, Callaerts-Vegh Z, Trabzuni D, Bossers K, Verhaagen J, Ryten M, Munck S, D'Hooge R, Swaab DF, Hardy J, Saido TC, De Strooper B, Thathiah A. Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models. Sci Transl Med. 2015 Oct 14;7(309):309ra164. PubMed.
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University of Kansas
This study provides an important validation of Gpr3 as a therapeutic target for AD. The results are impressive, with reduced amyloid and improved cognitive function in multiple AD mouse models. However, as the authors themselves point out, it will be critical to show that these effects occur upon pharmacological inhibition in adult mice, rather than on genetic deletion from conception onward.
More fundamentally, there must be more convincing evidence from clinical trials that targeting Aβ or Aβ production will truly slow disease progression or delay disease onset. How early must anti-amyloid therapeutics be given in order to provide clear benefit? If AD becomes a tau-driven process years before disease onset, then targeting Aβ, either directly with antibodies or indirectly through Gpr3, will not be effective. We all keenly await the results of the various ongoing AD prevention trials.
View all comments by Michael WolfeRIKEN Center for Brain Science
As a co-author, I would like to comment that BBB-permeable Gpr3-specific antagonist(s) without any side effect can become ideal anti-Aβ medication(s). They could be less expensive than therapeutic antibodies. A failure of Aβ immunotherapy could generate a serious negative social impact on the Aβ hypothesis, which, in my view, is already scientifically proven. We should realize that there are many options, such as GPCR agonists and antagonists, for the anti-Aβ strategy in addition to immunotherapy, to which the concern about the preventive timing raised by Michael Wolfe in the previous comments also applies.
View all comments by Takaomi SaidoUniversity of Kansas
To clarify my comments, I agree with Takaomi Saido that the Aβ hypothesis is essentially proven scientifically by the FAD mutations in APP and the presenilins.
My point is that Aβ may be an impractical target, because it may need to be reduced or blocked so many years in advance before the pathogenic process becomes primarily tau-driven. While ongoing trials may ultimately show clear disease modification (and I certainly hope that they do), the possibility remains that they may not. The failure of these trials, especially if there are no major safety concerns and clear evidence for target engagement, would make it very difficult to convince pharma, venture capitalists, and funding agencies that they should pour more money, resources, and time into targeting Aβ. Presently this remains an unresolved issue, and we must await the results of the various prevention trials.
In the meantime, pursuing other means of targeting Aβ, such as via Gpr3, is certainly worthwhile, but we should be prepared for blow-back and major obstacles to continuing this avenue of translational investigation in the event anti-Aβ agents currently in the pipeline fail in the clinic.
View all comments by Michael WolfeHanyang University
The current study by the groups of De Strooper and Thathiah adds further details about the potential mechanism involved in regulation of Aβ precursor protein (APP) processing by G protein-coupled receptors (GPCRs) and is based on their previous findings showing that the orphan GPCR 3 (GPR3) modulates Aβ peptide generation in neurons (Thathiah and De Strooper, 2009; Thathiah et al., 2009; Thathiah and De Strooper, 2011; Thathiah et al., 2013).
In fact, this is not a completely new idea, as Nishimoto and colleagues had shown in 1993 a clear link between APP and GPCR signaling pathways and that the cytosolic part of APP can bind to and activate Go (a major GTP-binding protein in brain) in a ligand-dependent manner (Nishimoto et al., 1993; Okamoto et al., 1995,1996). However, the connections between APP and GPCRs had been neglected for a long time and re-emerged only recently with the accumulation of new evidence that linked APP with GPCRs and the addition of further details on APP processing affected by GPCR systems. It is thus of utmost interest for the pharmaceutical industry due to the relative easy access of these receptors to pharmaceuticals (see reviews: Thathiah and De Strooper, 2009; Heese, 2013; Thathiah and De Strooper, 2011).
Indeed, the current data by Huang et al. add further evidence about the significance of GPCRs and APP processing. Here, they demonstrate that genetic deletion of GPR3 in AD mouse model reduces amyloid plaques and alleviates cognitive deficits in these mice. Furthermore, human AD postmortem brain-tissue samples showed a correlation between elevated GPR3 and AD progression, which is in line with reduced p60TRP (another pivotal GPCR-modulating protein) expression in AD brains (Heese et al., 2004).
Similarly, Pei and colleagues showed a few years ago that a GPCR/secretase complex regulates β- and γ-secretase specificity for Aβ production and contributes to AD pathogenesis (Teng et al., 2010). Specifically, they demonstrated that the δ-opioid receptor (OPRD1, otherwise known as DOR) promotes the β- and γ-secretase-mediated processing of APP and that knockdown of OPRD1 reduces the secretase activities and ameliorates Aβ pathology and Aβ-dependent behavioral deficits, without affecting the processing of Notch, N-cadherin, or APLP in AD model mice (Teng et al., 2010), and thus suggested that intervention in either the formation or trafficking of the GPCR/secretase complex could eventually lead to a new strategy for the treatment of AD, potentially with fewer side effects than current treatments.
Further extensive research has revealed numerous interacting partners of GPCRs, including the GPCR-associated sorting protein (GPRASP) family members (Abu-Helo and Simonin, 2010; Moser et al., 2010). p60TRP (also known as GPRASP3, GASP3, or BHLHB9) is a member of this GPRASP family (Heese et al., 2004) that also regulates the endocytic recycling of OPRD1 (Mishra and Heese, 2011). A transgenic p60TRP in vivo imaging mouse model has been used recently to show that p60TRP can mediate a reduction in the phosphorylation of APP, a reduction in the activities of β- and γ-secretases (Bace1/Psen2), and an increase in the activity of protein phosphatase PP2A, while increasing synaptic connections in the brain and enhancing cognitive functions in these mice (Mishra and Heese, 2011; Manavalan et al., 2013).
Taken together, the integration of various data obtained thus far may open new avenues for the treatment of AD via an APP-GPCR-linkage pathway. Since a silver bullet might not soon be found for the treatment of AD, it is time to think about alternative approaches that may help treat patients suffering from this devastating disease. The paper by Huang et al. provides promising data that supports this idea.
References:
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