QBI Research Presentation: GPCR Dysfunction in Alzheimer’s Disease
Event Details
- Date:
- Wednesday, 24 June 2015 - Wednesday, 24 June 2015
- Time:
- 1:00 pm - 1:45 pm
- Room:
- QBI Level 7 Auditorium
- UQ Location:
- Queensland Brain Institute (St Lucia)
- URL:
- http://www.qbi.uq.edu.au/neuroscience-seminars
- Event category(s):
Event Contact
- Name:
- Ms Deirdre Wilson
- Phone:
- 66300
- Email:
- d.wilson5@uq.edu.au
- Org. Unit:
- Queensland Brain Institute
Event Description
- Full Description:
- Dr Amantha Thathiah
Department of Human Genetics Katholieke University, Leuven, Belgium
Title: GPCR Dysfunction in Alzheimer’s Disease
Abstract:
G protein-coupled receptors (GPCRs) GPCRs are involved in numerous neurotransmitter systems which are disrupted in the brains of Alzheimer’s disease (AD) patients. GPCRs are also associated with multiple stages of β-amyloid precursor protein (APP) proteolysis, including modulation of the α-, b-, and γ-secretase processing of APP and regulation of amyloid-β (Aβ) degradation and Aβ-mediated neurotoxicity, indicating an intimate association between GPCRs and the molecular pathways involved in AD. We recently identified the orphan GPCR GPR3 as a modulator of γ-secretase activity and Aβ generation in vitro and in vivo in four AD transgenic mouse models. Further studies indicate that G protein-coupling and signaling are not involved in the GPR3-mediated effect on Aβ generation; however, a small family of multifunctional GPCR regulatory proteins known as the β-arrestins, which play an almost universal role in facilitating traditional GPCR desensitization, are also capable of initiating distinct signals, conveying receptor subtype-specific signaling events. These signals are often both spatially and temporally distinct and result in unique cellular and physiological or pathophysiological consequences. As mediators of GPCR desensitization, trafficking and cell signaling, we hypothesized that the β arrestins provide a putative basis to understand the link between GPCRs and Aβ generation through regulation of the γ-secretase complex. We determined that β arrestin 2 levels are elevated in two independent cohorts of patients with AD. Genetic deletion of Arrb2 (β-arrestin 2) leads to a reduction in accumulation of the Aβ peptide in an AD mouse model. Consistent with these observations, endogenous murine Aβ generation is also reduced in Arrb2-/- mice. Elucidation of the mechanism of theβ-arrestin 2-mediated effect on Aβ levels indicates that recruitment of β arrestin 2 to two GPCRs implicated in the pathogenesis of AD, GPR3 and the β -adrenergic receptor (β2-AR), is required for the promotion of Aβ release. Collectively, these studies suggest that identification of pharmacologic agents that selectively modulate the interaction between β-arrestin 2 and GPCRs, such as GPR3 and the β2-AR, may ultimately be a worthwhile therapeutic strategy for AD and could prove to be beneficial in prevention of the adverse side effects associated with direct γ-secretase inhibition, e.g. Notch signaling or APP-CTF accumulation. As it becomes increasingly evident that presymptomatic and/or very early symptomatic treatments are necessary to prevent the onset of dementia, these studies suggest a previously unexplored avenue involving β-arrestin 2 inhibition for therapeutic intervention and prevention in Alzheimer’s disease.
Directions to UQ
- Google Map:
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- Directions:
- St Lucia Campus | Gatton campus.
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