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

The mechanism whereby activation of G protein–coupled receptors (GPCRs) increase the production of amyloid-β (Aβ) peptide remains unclear. Here Bart De Strooper and colleagues show that the GPCR adaptor protein β-arrestin 2 promotes Aβ production by associating with APH-1A and increasing γ-secretase activity. Overexpression of β-arrestin 2 increases Aβ generation, whereas mice lacking β-arrestin 2 have reduced amyloid accumulation. Moreover, expression of β-arrestin 2 is elevated in individuals with Alzheimer's disease, suggesting a potential therapeutic target aimed at reducing amyloid production.