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Endoplasmic Reticulum Enrollment in Alzheimer’s Disease

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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.

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Abbreviations

AD:

Alzheimer’s disease

AICD:

Amyloid precursor protein intracellular domain

APP:

Amyloid precursor protein

ASK1:

Apoptosis signal-regulating kinase

ATF:

Activating transcription factor

Aβ:

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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Acknowledgments

This work was supported by grants PTDC/BIA-BCM/67922/2006 and PTDC/SAU-NMC/117877/2010 from Fundação para a Ciência e a Tecnologia (FCT), Lisbon, Portugal. RJSV and AFN were recipients of PhD and postdoctoral fellowships SFRH/BD/30467/2006 and SFRH/BPD/34603/2007, respectively, from FCT.

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Correspondence to Cecília M. P. Rodrigues.

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Viana, R.J.S., Nunes, A.F. & Rodrigues, C.M.P. Endoplasmic Reticulum Enrollment in Alzheimer’s Disease. Mol Neurobiol 46, 522–534 (2012). https://doi.org/10.1007/s12035-012-8301-x

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  • DOI: https://doi.org/10.1007/s12035-012-8301-x

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