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Cell Res. 2013 Mar;23(3):351-65. doi: 10.1038/cr.2012.167. Epub 2012 Dec 4.

β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology.

Author information

1
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.

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.

PMID:
23208420
PMCID:
PMC3587707
DOI:
10.1038/cr.2012.167
[Indexed for MEDLINE]
Free PMC Article

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