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
Article

Abstract

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.

Keywords

Amyloid β Caspases Chaperones JNK Tauroursodeoxycholic acid 

Abbreviations

AD

Alzheimer’s disease

AICD

Amyloid precursor protein intracellular domain

APP

Amyloid precursor protein

ASK1

Apoptosis signal-regulating kinase

ATF

Activating transcription factor

Amyloid β

BACE

β-site of APP cleaving enzyme

Bcl-2

B-cell leukemia/lymphoma 2

CHOP

C/EBP homologous protein

eIF2α

Eukaryotic translation initiation factor 2α

ER

Endoplasmic reticulum

ERAD

Endoplasmic reticulum-associated degradation

GRP

Glucose-regulated protein

GSK-3β

Glycogen synthase kinase-3β

IRE1

Inositol-requiring kinase 1

JNK

c-Jun N-terminal kinase

MAPK

Mitogen-activated protein kinase

MVB

Multivesicular body

NFT

Neurofibrillary tangle

PERK

Protein kinase-like endoplasmic reticulum kinase

PS1

Presenilin-1

RyR

Ryanodine receptor

TRAF2

Receptor-associated factor 2

TUDCA

Tauroursodeoxycholic acid

UPR

Unfolded protein response

UPS

Ubiquitin–proteasome system

XBP1

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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