title: β-arrestin1 regulates γ-secretase complex assembly and modulates amyloid-β pathology.
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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Liu
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhao
authors.forename: Xianglu
authors.initials: X
authors.lastname: Zeng
authors.forename: Koen
authors.initials: K
authors.lastname: Bossers
authors.forename: Dick F
authors.initials: DF
authors.lastname: Swaab
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Gang
authors.initials: G
authors.lastname: Pei
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D000071557:beta-Arrestins
chemical_list: D016229:Amyloid beta-Peptides; D019390:Arrestins; D000071557:beta-Arrestins; D053829:Amyloid Precursor Protein Secretases