β-Arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology

Alzheimer's disease (AD) is a progressive and complex neurodegenerative disease in which the gamma-secretase-mediated amyloid-beta (A beta) pathology plays an important role. We found that a multifunctional protein, beta-arrestin1, facilitated the formation of NCT/APH-1 (anterior pharynx-defective phenotype 1) precomplex and mature gamma-secretase complex through its functional interaction with APH-1. Deficiency of beta-arrestin1 or inhibition of binding of beta-arrestin1 with APH-1 by small peptides reduced A beta production without affecting Notch processing. Genetic ablation of beta-arrestin1 diminished A beta pathology and behavioral deficits in transgenic AD mice. Moreover, in brains of sporadic AD patients and transgenic AD mice, the expression of beta-arrestin1 was upregulated and correlated well with neuropathological severity and senile A beta plaques. Thus, our study identifies a regulatory mechanism underlying both gamma-secretase assembly and AD pathogenesis, and indicates that specific reduction of A beta pathology can be achieved by regulation of the gamma-secretase assembly.