Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer’s disease mouse models

Abstract

The orphan G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) GPR3 regulates activity of the γ-secretase complex in the absence of an effect on Notch proteolysis, providing a potential therapeutic target for Alzheimer's disease (AD). However, given the vast resources required to develop and evaluate any new therapy for AD and the multiple failures involved in translational research, demonstration of the pathophysiological relevance of research findings in multiple disease-relevant models is necessary before initiating costly drug development programs. We evaluated the physiological consequences of loss of Gpr3 in four AD transgenic mouse models, including two that contain the humanized murine Aβ sequence and express similar amyloid precursor protein (APP) levels as wild-type mice, thereby reducing potential artificial phenotypes. Our findings reveal that genetic deletion of Gpr3 reduced amyloid pathology in all of the AD mouse models and alleviated cognitive deficits in APP/PS1 mice. Additional three-dimensional visualization and analysis of the amyloid plaque burden provided accurate information on the amyloid load, distribution, and volume in the structurally intact adult mouse brain. Analysis of 10 different regions in healthy human postmortem brain tissue indicated that GPR3 expression was stable during aging. However, two cohorts of human AD postmortem brain tissue samples showed a correlation between elevated GPR3 and AD progression. Collectively, these studies provide evidence that GPR3 mediates the amyloidogenic proteolysis of APP in four AD transgenic mouse models as well as the physiological processing of APP in wild-type mice, suggesting that GPR3 may be a potential therapeutic target for AD drug development.

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

“…Subsequent findings from the same research group provided further validation of the role of GPR3 in AD (Thathiah et al 2013; Huang et al 2015). An array of functional experiments proved that GPR3 regulates Aβ generation via β-arrestin2 via a G protein-independent mechanism (Thathiah et al 2013).…”

“…Both Aβ 1–40 and Aβ 1–42 levels increased in a dose dependent manner with GPR3 expression. Moreover, the expression of GPR3 is elevated in the postmortem brain of sporadic AD patients and this upregulation correlates with the progression of the disease (Thathiah et al 2009; Huang et al 2015). …”

“…Pursuing a translational approach, the effect of GPR3 was examined in four different AD transgenic mice models (Huang et al 2015). An exploration of the role of this receptor in amyloid pathology, as well as, in behavioral studies was undertaken.…”

Viral vectors for therapy of neurologic diseases

“…The most straightforward strategies have aimed at directly inhibiting the production of neurotoxic species of amyloid, either via viral vector expression of Aβ degrading enzymes, such as Neprilysin (Li et al, 2015; Lebson et al, 2010), or anti-Aβ single-chain antibodies to achieve passive immunization (Levites et al, 2015). Alternatively, targeting the cleavage of APP has been attempted, with genetic transfer of siRNA specific for β-secretase (Nawrot, 2004) or shRNA to knock-down the orphan G protein-coupled receptor that regulates activity of γ-secretase (Huang et al, 2015a), the first and second enzymes, respectively, controlling the proteolysis of APP to produce the neurotoxic amyloid peptides, respectively. Additionally, AAV-mediated expression of CD74, a chaperone that directly binds to the APP, also prevents the accumulation of Aβ in the hippocampus and improves cognitive deficits of AD mice (Kiyota et al, 2015).…”

1,2,3,4,6-penta-O-galloyl-β-d-glucopyranose binds to the N-terminal metal binding region to inhibit amyloid β-protein oligomer and fibril formation

“…1–8 A β proteins are derived from sequential endoproteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretase 9–12 to generate alloforms of 37–43 amino acid. A β 1-40 and A β 1-42 (Scheme 1) are the dominant forms and the main targets in the amyloid cascade hypothesis.…”