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

Xiaosong Liu, Xiaohui Zhao, Xianglu Zeng, Koen Bossers, Dick F. Swaab, Jian Zhao, Gang Pei

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)351-365
Number of pages15
JournalCell Research
Volume23
Issue number3
DOIs
StatePublished - Mar 2013

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