Induction of the unfolded protein response and cell death pathway in Alzheimer's disease, but not in aged Tg2576 mice

Exp Mol Med. 2010 May 31;42(5):386-94. doi: 10.3858/emm.2010.42.5.040.


The endoplasmic reticulum (ER) stress results from disrupted protein folding triggered by protein mutation or oxidation, reduced proteasome activity, and altered Ca2+ homeostasis. ER stress is accompanied by activation of the unfolded protein response (UPR) and cell death pathway. We examined if the UPR and cell death pathway would be activated in Alzheimer's disease (AD). RT-PCR experiments revealed increased splicing of X-box binding protein-1 (XBP-1), an UPR transcription factor, in AD compared with age-matched control. Among target genes of XBP-1, expression of protein disulfide isomerase (PDI), but not glucose-regulated protein 78 (GRP78), was increased in AD, suggesting disturbed activation of the UPR in AD. C/EBP homologous protein (CHOP), caspase-3, caspase-4, and caspase-12, downstream mediators of cell death pathway, were activated in AD. Neither the UPR nor cell death pathway was induced in aged Tg2576 mice, a transgenic mouse model of Alzheimer's disease that reveals both plaque pathology and some cognitive deficits. The present study suggests that disturbed induction of the UPR and activation of the pro-apoptotic proteins contribute to neuropathological process in AD irrespective of amyloid beta and senile plaque.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • Aging / pathology
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Blotting, Western
  • Cell Death / genetics*
  • DNA-Binding Proteins / analysis*
  • Endoplasmic Reticulum / genetics
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Heat-Shock Proteins / analysis
  • Humans
  • Immunohistochemistry
  • Male
  • Mice
  • Mice, Transgenic
  • Middle Aged
  • Protein Disulfide-Isomerases / analysis
  • Regulatory Factor X Transcription Factors
  • Stress, Physiological / genetics
  • Transcription Factors / analysis*
  • Unfolded Protein Response / genetics*
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Protein Disulfide-Isomerases
  • molecular chaperone GRP78