Enhanced generation of intracellular Abeta42 amyloid peptide by mutation of presenilins PS1 and PS2

Eur J Neurosci. 2004 Jan;19(2):258-264. doi: 10.1111/j.0953-816x.2003.03135.x.


The accumulation of amyloid beta-peptide (Abeta) in the brain is a critical pathological process in Alzheimer's disease (AD). Recent studies have implicated intracellular Abeta in neurodegeneration in AD. To investigate the generation of intracellular Abeta, we established human neuroblastoma SH-SY5Y cells stably expressing wild-type amyloid precursor protein (APP), Swedish mutant APP, APP plus presenilin 1 (PS1) and presenilin 2 (PS2; wild-type or familial AD-associated mutant), and quantified intracellular Abeta40 and Abeta42 in formic acid extracts by sensitive Western blotting. Levels of both intracellular Abeta40 and Abeta42 were 2-3-fold higher in cells expressing Swedish APP, compared with those expressing wild-type APP. Intracellular Abeta42/Abeta40 ratios were approximately 0.5 in these cells. These ratios were increased markedly in cells expressing mutant PS1 or PS2 compared with those expressing their wild-type counterparts, consistent with the observed changes in secreted Abeta42/Abeta40 ratios. High total levels of intracellular Abeta were observed in cells expressing mutant PS2 because of a marked elevation of Abeta42. Immunofluorescence staining additionally revealed more intense Abeta42 immunoreactivity in mutant PS2-expressing cells than in wild-type cells, which was partially colocalized with immunoreactivity for the trans-Golgi network and endosomes. The data collectively indicate that PS mutations promote the accumulation of intracellular Abeta42, which appears to be localized in multiple subcellular compartments.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / biosynthesis*
  • Amyloid beta-Peptides / genetics
  • Cell Line, Tumor
  • Humans
  • Intracellular Fluid / metabolism*
  • Membrane Proteins / genetics*
  • Mutation / genetics*
  • Peptide Fragments / biosynthesis*
  • Peptide Fragments / genetics
  • Presenilin-1
  • Presenilin-2


  • Amyloid beta-Peptides
  • Membrane Proteins
  • PSEN1 protein, human
  • PSEN2 protein, human
  • Peptide Fragments
  • Presenilin-1
  • Presenilin-2
  • amyloid beta-protein (1-42)