| First Author | Thathiah A | Year | 2013 |
| Journal | Nat Med | Volume | 19 |
| Issue | 1 | Pages | 43-9 |
| PubMed ID | 23202293 | Mgi Jnum | J:318164 |
| Mgi Id | MGI:6858526 | Doi | 10.1038/nm.3023 |
| Citation | Thathiah A, et al. (2013) beta-arrestin 2 regulates Abeta generation and gamma-secretase activity in Alzheimer's disease. Nat Med 19(1):43-9 |
| abstractText | 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 (Abeta) peptide generation, whereas genetic silencing of Arrb2 (encoding beta-arrestin 2) reduces generation of Abeta 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 Abeta(40) and Abeta(42). Two GPCRs implicated previously in Alzheimer's disease (GPR3 and the beta(2)-adrenergic receptor) mediate their effects on Abeta 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. |
