title: β-arrestin 2 regulates Aβ generation and γ-secretase activity in Alzheimer's disease.
abstract: 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.
authors.affiliation: Vlaams Instituut voor Biotechnologie Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Amantha
authors.initials: A
authors.lastname: Thathiah
authors.forename: Katrien
authors.initials: K
authors.lastname: Horré
authors.forename: An
authors.initials: A
authors.lastname: Snellinx
authors.forename: Elke
authors.initials: E
authors.lastname: Vandewyer
authors.forename: Yunhong
authors.initials: Y
authors.lastname: Huang
authors.forename: Marta
authors.initials: M
authors.lastname: Ciesielska
authors.forename: Gerdien
authors.initials: G
authors.lastname: De Kloe
authors.forename: Sebastian
authors.initials: S
authors.lastname: Munck
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D016229:Amyloid beta-Peptides; C000605258:Arrb2 protein, mouse; D019390:Arrestins; C494613:GPR3 protein, mouse; D018343:Receptors, Adrenergic, beta-2; D043562:Receptors, G-Protein-Coupled; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D053829:Amyloid Precursor Protein Secretases