Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease

EMBO Mol Med. 2012 Jul;4(7):660-73. doi: 10.1002/emmm.201200243. Epub 2012 May 2.

Abstract

Inherited familial Alzheimer's disease (AD) is characterized by small increases in the ratio of Aβ42 versus Aβ40 peptide which is thought to drive the amyloid plaque formation in the brain of these patients. Little is known however whether ageing, the major risk factor for sporadic AD, affects amyloid beta-peptide (Aβ) generation as well. Here we demonstrate that the secretion of Aβ is enhanced in an in vitro model of neuronal ageing, correlating with an increase in γ-secretase complex formation. Moreover we found that peroxynitrite (ONOO(-)), produced by the reaction of superoxide anion with nitric oxide, promoted the nitrotyrosination of presenilin 1 (PS1), the catalytic subunit of γ-secretase. This was associated with an increased association of the two PS1 fragments, PS1-CTF and PS1-NTF, which constitute the active catalytic centre. Furthermore, we found that peroxynitrite shifted the production of Aβ towards Aβ(42) and increased the Aβ(42) /Aβ(40) ratio. Our work identifies nitrosative stress as a potential mechanistic link between ageing and AD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / enzymology*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / metabolism
  • Animals
  • Brain / metabolism
  • Catalytic Domain
  • Cells, Cultured
  • Cellular Senescence / drug effects*
  • Humans
  • Mice
  • Neurons / cytology
  • Neurons / metabolism*
  • Peptide Fragments / metabolism
  • Peroxynitrous Acid / pharmacology*
  • Presenilin-1 / chemistry
  • Presenilin-1 / metabolism
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Risk Factors
  • Superoxide Dismutase / antagonists & inhibitors
  • Superoxide Dismutase / genetics
  • Superoxide Dismutase / metabolism

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • Presenilin-1
  • RNA, Small Interfering
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • Peroxynitrous Acid
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Amyloid Precursor Protein Secretases