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.
journal_name
Cell Resjournal_title
Cell researchauthors
Liu X,Zhao X,Zeng X,Bossers K,Swaab DF,Zhao J,Pei Gdoi
10.1038/cr.2012.167subject
Has Abstractpub_date
2013-03-01 00:00:00pages
351-65issue
3eissn
1001-0602issn
1748-7838pii
cr2012167journal_volume
23pub_type
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