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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism*
  • Amyloid Precursor Protein Secretases / genetics
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Arrestins / genetics
  • Arrestins / metabolism*
  • Cells, Cultured
  • Enzyme-Linked Immunosorbent Assay
  • Immunohistochemistry
  • Mice
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • beta-Arrestins

Substances

  • Amyloid beta-Peptides
  • Arrestins
  • beta-Arrestins
  • Amyloid Precursor Protein Secretases