Molecular Neurobiology

, Volume 46, Issue 2, pp 522–534

Endoplasmic Reticulum Enrollment in Alzheimer’s Disease

  • Ricardo J. S. Viana
  • Ana F. Nunes
  • Cecília M. P. Rodrigues


Alzheimer’s disease (AD) poses a huge challenge for society and health care worldwide as molecular pathogenesis of the disease is poorly understood and curative treatment does not exist. The mechanisms leading to accelerated neuronal cell death in AD are still largely unknown, but accumulation of misfolded disease-specific proteins has been identified as potentially involved. In the present review, we describe the essential role of endoplasmic reticulum (ER) in AD. Despite the function that mitochondria may play as the central major player in the apoptotic process, accumulating evidence highlights ER as a critical organelle in AD. Stress that impairs ER physiology leads to accumulation of unfolded or misfolded proteins, such as amyloid β (Aβ) peptide, the major component of amyloid plaques. In an attempt to ameliorate the accumulation of unfolded proteins, ER stress triggers a protective cellular mechanism, which includes the unfolded protein response (UPR). However, when activation of the UPR is severe or prolonged enough, the final cellular outcome is pathologic apoptotic cell death. Distinct pathways can be activated in this process, involving stress sensors such as the JNK pathway or ER chaperones such as Bip/GRP94, stress modulators such as Bcl-2 family proteins, or even stress effectors such as caspase-12. Here, we detail the involvement of the ER and associated stress pathways in AD and discuss potential therapeutic strategies targeting ER stress.


Amyloid β Caspases Chaperones JNK Tauroursodeoxycholic acid 



Alzheimer’s disease


Amyloid precursor protein intracellular domain


Amyloid precursor protein


Apoptosis signal-regulating kinase


Activating transcription factor

Amyloid β


β-site of APP cleaving enzyme


B-cell leukemia/lymphoma 2


C/EBP homologous protein


Eukaryotic translation initiation factor 2α


Endoplasmic reticulum


Endoplasmic reticulum-associated degradation


Glucose-regulated protein


Glycogen synthase kinase-3β


Inositol-requiring kinase 1


c-Jun N-terminal kinase


Mitogen-activated protein kinase


Multivesicular body


Neurofibrillary tangle


Protein kinase-like endoplasmic reticulum kinase




Ryanodine receptor


Receptor-associated factor 2


Tauroursodeoxycholic acid


Unfolded protein response


Ubiquitin–proteasome system


X-box-binding protein 1


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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ricardo J. S. Viana
    • 1
  • Ana F. Nunes
    • 1
  • Cecília M. P. Rodrigues
    • 1
    • 2
  1. 1.Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of PharmacyUniversity of LisbonLisbonPortugal
  2. 2.Department of Biochemistry and Human Biology, Faculty of PharmacyUniversity of LisbonLisbonPortugal

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