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

Nat Med. 2013 Jan;19(1):43-9. doi: 10.1038/nm.3023. Epub 2012 Dec 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / biosynthesis*
  • Animals
  • Arrestins / genetics
  • Arrestins / metabolism*
  • CHO Cells
  • Cell Line
  • Cricetinae
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • ARRB2 protein, human
  • Amyloid beta-Peptides
  • Arrb2 protein, mouse
  • Arrestins
  • GPR3 protein, mouse
  • Receptors, Adrenergic, beta-2
  • Receptors, G-Protein-Coupled
  • beta-Arrestin 2
  • beta-Arrestins
  • Amyloid Precursor Protein Secretases