Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid β-peptide (1-42), H2O2 and kainic acid: Implications for Alzheimer's disease

Hafiz Mohmmad Abdul, Rukhsana Sultana, Jeffrey N. Keller, Daret K. St. Clair, William R. Markesbery, D. Allan Butterfield

Research output: Contribution to journalArticlepeer-review

111 Scopus citations

Abstract

Oxidative stress is observed in Alzheimer's disease (AD) brain, including protein oxidation and lipid peroxidation. One of the major pathological hallmarks of AD is the brain deposition of amyloid beta-peptide (Aβ). This 42-mer peptide is derived from the β-amyloid precursor protein (APP) and is associated with oxidative stress in vitro and in vivo. Mutations in the PS-1 and APP genes, which increase production of the highly amyloidogenic amyloid β-peptide (Aβ42), are the major causes of early onset familial AD. Several lines of evidence suggest that enhanced oxidative stress, inflammation, and apoptosis play important roles in the pathogenesis of AD. In the present study, primary neuronal cultures from knock-in mice expressing mutant human PS-1 and APP were compared with those from wild-type mice, in the presence or absence of various oxidizing agents, viz, Aβ(1-42), H2O 2 and kainic acid (KA). APP/PS-1 double mutant neurons displayed a significant basal increase in oxidative stress as measured by protein oxidation, lipid peroxidation, and 3-nitrotyrosine when compared with the wild-type neurons (p < 0.0005). Elevated levels of human APP, PS-1 and Aβ(1-42) were found in APP/PS-1 cultures compared with wild-type neurons. APP/PS-1 double mutant neuron cultures exhibited increased vulnerability to oxidative stress, mitochondrial dysfunction and apoptosis induced by Aβ(1-42), H 2O2 and KA compared with wild-type neuronal cultures. The results are consonant with the hypothesis that Aβ(1-42)-associated oxidative stress and increased vulnerability to oxidative stress may contribute significantly to neuronal apoptosis and death in familial early onset AD.

Original languageEnglish
Pages (from-to)1322-1335
Number of pages14
JournalJournal of Neurochemistry
Volume96
Issue number5
DOIs
StatePublished - Mar 2006

Keywords

  • Alzheimer's disease
  • Amyloid precursor protein
  • Oxidative stress
  • Presenilin-1
  • β-amyloid peptide (1-42)

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Mutations in amyloid precursor protein and presenilin-1 genes increase the basal oxidative stress in murine neuronal cells and lead to increased sensitivity to oxidative stress mediated by amyloid β-peptide (1-42), H2O2 and kainic acid: Implications for Alzheimer's disease'. Together they form a unique fingerprint.

Cite this