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

beta-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 beta-arrestin 2 expression is elevated in two independent cohorts of individuals with Alzheimer's disease. Overexpression of beta-arrestin 2 leads to an increase in amyloid-beta (A beta) peptide generation, whereas genetic silencing of Arrb2 (encoding beta-arrestin 2) reduces generation of A beta 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 A beta(40) and A beta(42). Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the beta(2)-adrenergic receptor) mediate their effects on A beta generation through interaction with beta-arrestin 2. beta-arrestin 2 physically associates with the Aph-1a subunit of the gamma-secretase complex and redistributes the complex toward detergent-resistant membranes, increasing the catalytic activity of the complex. Collectively, these studies identify beta-arrestin 2 as a new therapeutic target for reducing amyloid pathology and GPCR dysfunction in Alzheimer's disease.