β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer’s disease

Thathiah et al. Molecular Neurodegeneration 2013, 8(Suppl 1):P41 http://www.molecularneurodegeneration.com/content/8/S1/P41 POSTER PRESENTATION Open Access b-arrestin 2 regulates Ab generation and g-secretase activity in Alzheimer’s disease Amantha Thathiah1,2*, Katrien Horre1,2, An Snellinx1,2, Elke Vandewyer1,2, Yunhong Huang1,2, Marta Ciesielska1,2, Gerdien De Kloe1,3, Sebastian Munck1,2, Bart De Strooper1,2 From Molecular Neurodegeneration: Basic biology and disease pathways Cannes, France. 10-12 September 2013 Deficits in several neurotransmitter systems are characteristic features of the brains of AD patients. The majority of neurotransmitters communicate information to cells via G protein-coupled receptors (GPCRs) or 7-transmembrane receptors (7TMRs). It has recently been appreciated that a small family of multifunctional GPCR regulatory known as the b-arrestins which play an almost universal role in facilitating traditional GPCR desensitization, are also capable of initiating distinct signals in their own right, 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, the b-arrestins provide a putative basis to understand GPCR dysfunction in AD. Here, we report that b-arrestin 2 levels are elevated in two independent cohorts of patients with AD. Genetic deletion of Arrb2 (b-arrestin 2) reduces accumulation of the amyloid-b (Ab) peptide in an AD mouse model. Consistent with these observations, endogenous murine Ab generation is also reduced in Arrb2-/- mice. Elucidation of the mechanism of the b-arrestin 2-mediated effect on Ab levels indicates that recruitment of b-arrestin 2 to two GPCRs implicated in the pathogenesis of AD, GPR3 and the b2-adrenergic receptor (b2-AR), is required for the promotion of Ab release. Collectively, these studies identify b-arrestin 2 as a novel avenue for targeting amyloid pathology and GPCR dysfunction in AD. Published: 13 September 2013 doi:10.1186/1750-1326-8-S1-P41 Cite this article as: Thathiah et al.: b-arrestin 2 regulates Ab generation and g-secretase activity in Alzheimer’s disease. Molecular Neurodegeneration 2013 8(Suppl 1):P41. Submit your next manuscript to BioMed Central and take full advantage of: • Convenient online submission • Thorough peer review Authors’ details 1 VIB Center for the Biology of Disease, Leuven, Belgium. 2Center for Human Genetics, University of Leuven (KU Leuven), Leuven, Beigium. 3Neuroscience Medicinal Chemistry, Janssen Research and Development, a Division of Janssen Pharmaceutica NV, Beerse, Belgium. 1 VIB Center for the Biology of Disease, Leuven, Belgium Full list of author information is available at the end of the article • No space constraints or color figure charges • Immediate publication on acceptance • Inclusion in PubMed, CAS, Scopus and Google Scholar • Research which is freely available for redistribution Submit your manuscript at www.biomedcentral.com/submit © 2013 Thathiah et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.  (...truncated)