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

• Published in: Nature medicine Vol. 19; no. 1; pp. 43 - 49
• Main Authors: Thathiah, Amantha, Horré, Katrien, Snellinx, An, Vandewyer, Elke, Huang, Yunhong, Ciesielska, Marta, De Kloe, Gerdien, Munck, Sebastian, De Strooper, Bart
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2013; Nature Publishing Group
• Subjects: 692/420; 692/699/375/365/1283; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - biosynthesis; Amyloid Precursor Protein Secretases - metabolism; Animals; Arrestins; Arrestins - genetics; Arrestins - metabolism; beta-Arrestin 2; beta-Arrestins; Biomedicine; Cancer Research; Care and treatment; Cell Line; CHO Cells; Cricetinae; Health aspects; HEK293 Cells; HeLa Cells; Humans; Infectious Diseases; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Medicine; Neurosciences; Properties; Receptors, Adrenergic, beta-2 - metabolism; Receptors, G-Protein-Coupled - metabolism; Signal Transduction; Belgium
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3023

The mechanism whereby activation of G protein–coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production. β-arrestins are associated with numerous aspects of G protein–coupled receptor (GPCR) signaling and regulation and accordingly influence diverse physiological and pathophysiological processes. Here we report that β-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of β-arrestin 2 leads to an increase in amyloid-β (Aβ) peptide generation, whereas genetic silencing of Arrb2 (encoding β-arrestin 2) reduces generation of Aβ in cell cultures and in Arrb2 −/− mice. Moreover, in a transgenic mouse model of Alzheimer's disease, genetic deletion of Arrb2 leads to a reduction in the production of Aβ 40 and Aβ 42 . Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the β 2 -adrenergic receptor) mediate their effects on Aβ generation through interaction with β-arrestin 2. β-arrestin 2 physically associates with the Aph-1a subunit of the γ-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify β-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.