부산대학교 도서관

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