Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness

Cell Stem Cell. 2013 Apr 4;12(4):487-96. doi: 10.1016/j.stem.2013.01.009. Epub 2013 Feb 21.


Oligomeric forms of amyloid-β peptide (Aβ) are thought to play a pivotal role in the pathogenesis of Alzheimer's disease (AD), but the mechanism involved is still unclear. Here, we generated induced pluripotent stem cells (iPSCs) from familial and sporadic AD patients and differentiated them into neural cells. Aβ oligomers accumulated in iPSC-derived neurons and astrocytes in cells from patients with a familial amyloid precursor protein (APP)-E693Δ mutation and sporadic AD, leading to endoplasmic reticulum (ER) and oxidative stress. The accumulated Aβ oligomers were not proteolytically resistant, and docosahexaenoic acid (DHA) treatment alleviated the stress responses in the AD neural cells. Differential manifestation of ER stress and DHA responsiveness may help explain variable clinical results obtained with the use of DHA treatment and suggests that DHA may in fact be effective for a subset of patients. It also illustrates how patient-specific iPSCs can be useful for analyzing AD pathogenesis and evaluating drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / chemistry
  • Amyloid beta-Peptides / metabolism*
  • Cell Differentiation
  • Cerebral Cortex / pathology
  • Docosahexaenoic Acids / pharmacology*
  • Humans
  • Induced Pluripotent Stem Cells / drug effects
  • Induced Pluripotent Stem Cells / metabolism*
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism*
  • Models, Biological*
  • Mutant Proteins
  • Neurons / metabolism
  • Neurons / pathology
  • Oxidative Stress* / drug effects
  • Phenotype
  • Protein Structure, Quaternary


  • Amyloid beta-Peptides
  • Mutant Proteins
  • Docosahexaenoic Acids

Associated data

  • GEO/GSE43326
  • GEO/GSE43328
  • GEO/GSE43382