Skip to main content

Advertisement

SpringerLink
Log in

The unfolded protein response in Alzheimer’s disease

  • Review
  • Published:
Seminars in Immunopathology Aims and scope Submit manuscript

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by synaptic dysfunction and accumulation of amyloid-beta (Aβ) peptide, which are responsible for the progressive loss of memory. The mechanisms involved in neuron dysfunction in AD remain poorly understood. Recent evidence implicates the participation of adaptive responses to stress within the endoplasmic reticulum (ER) in the disease process, via a pathway known as the unfolded protein response (UPR). Here, we review the findings suggesting a functional role of ER stress in the etiology of AD. Possible therapeutic strategies to mitigate ER stress in the context of AD are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

Aβ:

Amyloid beta

AD:

Alzheimer’s disease

AICD:

APP intracellular domain

ALS:

Amyotrophic lateral sclerosis

APH1:

Anterior pharynx defective 1

APP:

Amyloid precursor protein

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

BACE1:

β-site APP cleaving enzyme-1

BiP/Grp78:

Glucose-related protein at 78 kDa

Cdk5:

Cyclin-dependent kinase 5

CHOP/GADD134:

C/EBP-homologous protein

eIF2α:

Eukaryotic translation initiator factor 2α

ER:

Endoplasmic reticulum

ERAD:

ER-associated degradation

FAD:

Familial AD

GCN2:

General control nonderepressible-2

GSK-3β:

Glycogen synthase kinase 3β

HD:

Huntington’s disease

HRI:

Hemin-regulated inhibitor kinase

Hsp70:

Heat-shock protein at 70 kDa

IP3-R:

IP3 receptors

IRE1:

Inositol-required 1

JNK:

c-Jun N-terminal kinases

NCSTN:

Nicastrin

NMDA-R:

N-methyl-d-aspartate receptor

PEN-2 or PSENEN:

Enhancer of presenilin-2

PERK:

Protein kinase RNA-like ER kinase

PD:

Parkinson’s disease

PDI:

Protein disulfide-isomerase

PKR:

Double-stranded RNA-dependent protein kinase

PMDs:

Protein misfolding disorders

PSEN:

Presenilin

RyRs:

Ryanodine receptors

SAD:

Sporadic AD

UPR:

Unfolded protein response

XBP1:

X box-binding protein 1

References

  1. Brown MK, Naidoo N (2012) The endoplasmic reticulum stress response in aging and age-related diseases. Front Physiol 3:263. doi:10.3389/fphys.2012.00263

    PubMed  Google Scholar 

  2. Soto C (2003) Unfolding the role of protein misfolding in neurodegenerative diseases. Nat Rev Neurosci 4(1):49–60. doi:10.1038/nrn1007

    PubMed  CAS  Google Scholar 

  3. Matus S, Glimcher LH, Hetz C (2011) Protein folding stress in neurodegenerative diseases: a glimpse into the ER. Curr Opin Cell Biol 23(2):239–252. doi:10.1016/j.ceb.2011.01.003

    PubMed  CAS  Google Scholar 

  4. Roussel BD, Kruppa AJ, Miranda E, Crowther DC, Lomas DA, Marciniak SJ (2013) Endoplasmic reticulum dysfunction in neurological disease. Lancet Neurol 12(1):105–118. doi:10.1016/S1474-4422(12)70238-7

    PubMed  CAS  Google Scholar 

  5. Balch WE, Morimoto RI, Dillin A, Kelly JW (2008) Adapting proteostasis for disease intervention. Science 319(5865):916–919. doi:10.1126/science.1141448

    PubMed  CAS  Google Scholar 

  6. Hetz C (2012) The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol 13(2):89–102. doi:10.1038/nrm3270

    PubMed  CAS  Google Scholar 

  7. Wang S, Kaufman RJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197(7):857–867. doi:10.1083/jcb.201110131

    PubMed  CAS  Google Scholar 

  8. Vidal RL, Figueroa A, Court FA, Thielen P, Molina C, Wirth C, Caballero B, Kiffin R, Segura-Aguilar J, Cuervo AM, Glimcher LH, Hetz C (2012) Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum Mol Genet. doi:10.1093/hmg/dds040

    Google Scholar 

  9. Colla E, Coune P, Liu Y, Pletnikova O, Troncoso JC, Iwatsubo T, Schneider BL, Lee MK (2012) Endoplasmic reticulum stress is important for the manifestations of alpha-synucleinopathy in vivo. J Neurosci 32(10):3306–3320. doi:10.1523/JNEUROSCI.5367-11.2012

    PubMed  CAS  Google Scholar 

  10. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112. doi:10.1038/nrm2101

    PubMed  CAS  Google Scholar 

  11. Selkoe DJ (2004) Cell biology of protein misfolding: the examples of Alzheimer’s and Parkinson’s diseases. Nat Cell Biol 6(11):1054–1061. doi:10.1038/ncb1104-1054

    PubMed  CAS  Google Scholar 

  12. Selkoe DJ (2004) Alzheimer disease: mechanistic understanding predicts novel therapies. Ann Intern Med 140(8):627–638

    PubMed  CAS  Google Scholar 

  13. Chyung JH, Raper DM, Selkoe DJ (2005) Gamma-secretase exists on the plasma membrane as an intact complex that accepts substrates and effects intramembrane cleavage. J Biol Chem 280(6):4383–4392. doi:10.1074/jbc.M409272200

    PubMed  CAS  Google Scholar 

  14. Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766

    PubMed  CAS  Google Scholar 

  15. Karran E, Mercken M, De Strooper B (2011) The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov 10(9):698–712. doi:10.1038/nrd3505

    PubMed  CAS  Google Scholar 

  16. Walsh DM, Selkoe DJ (2004) Oligomers on the brain: the emerging role of soluble protein aggregates in neurodegeneration. Protein Pept Lett 11(3):213–228

    PubMed  CAS  Google Scholar 

  17. Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL (2004) Synaptic targeting by Alzheimer’s-related amyloid beta oligomers. J Neurosci 24(45):10191–10200. doi:10.1523/JNEUROSCI.3432-04.2004

    PubMed  CAS  Google Scholar 

  18. Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci 27(4):796–807. doi:10.1523/JNEUROSCI.3501-06.2007

    PubMed  CAS  Google Scholar 

  19. Brito-Moreira J, Paula-Lima AC, Bomfim TR, Oliveira FB, Sepulveda FJ, De Mello FG, Aguayo LG, Panizzutti R, Ferreira ST (2011) Abeta oligomers induce glutamate release from hippocampal neurons. Curr Alzheimer Res 8(5):552–562

    PubMed  CAS  Google Scholar 

  20. De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL (2008) Alzheimer’s disease-type neuronal tau hyperphosphorylation induced by A beta oligomers. Neurobiol Aging 29(9):1334–1347. doi:10.1016/j.neurobiolaging.2007.02.029

    PubMed  Google Scholar 

  21. Paula-Lima AC, Adasme T, SanMartin C, Sebollela A, Hetz C, Carrasco MA, Ferreira ST, Hidalgo C (2011) Amyloid beta-peptide oligomers stimulate RyR-mediated Ca2+ release inducing mitochondrial fragmentation in hippocampal neurons and prevent RyR-mediated dendritic spine remodeling produced by BDNF. Antioxid Redox Signal 14(7):1209–1223. doi:10.1089/ars.2010.3287

    PubMed  CAS  Google Scholar 

  22. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298(5594):789–791. doi:10.1126/science.1074069

    PubMed  CAS  Google Scholar 

  23. McGowan E, Eriksen J, Hutton M (2006) A decade of modeling Alzheimer’s disease in transgenic mice. Trends Genet 22(5):281–289. doi:10.1016/j.tig.2006.03.007

    PubMed  CAS  Google Scholar 

  24. Vassar R, Kovacs DM, Yan R, Wong PC (2009) The beta-secretase enzyme BACE in health and Alzheimer’s disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29(41):12787–12794. doi:10.1523/JNEUROSCI.3657-09.2009

    PubMed  CAS  Google Scholar 

  25. Kimberly WT, LaVoie MJ, Ostaszewski BL, Ye W, Wolfe MS, Selkoe DJ (2003) Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2. Proc Natl Acad Sci U S A 100(11):6382–6387. doi:10.1073/pnas.1037392100

    PubMed  CAS  Google Scholar 

  26. Takasugi N, Tomita T, Hayashi I, Tsuruoka M, Niimura M, Takahashi Y, Thinakaran G, Iwatsubo T (2003) The role of presenilin cofactors in the gamma-secretase complex. Nature 422(6930):438–441. doi:10.1038/nature01506

    PubMed  CAS  Google Scholar 

  27. Reinhard C, Hebert SS, De Strooper B (2005) The amyloid-beta precursor protein: integrating structure with biological function. EMBO J 24(23):3996–4006. doi:10.1038/sj.emboj.7600860

    PubMed  CAS  Google Scholar 

  28. Busciglio J, Gabuzda DH, Matsudaira P, Yankner BA (1993) Generation of beta-amyloid in the secretory pathway in neuronal and nonneuronal cells. Proc Natl Acad Sci U S A 90(5):2092–2096

    PubMed  CAS  Google Scholar 

  29. LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci 8(7):499–509. doi:10.1038/nrn2168

    PubMed  CAS  Google Scholar 

  30. Weitz TM, Town T (2012) Microglia in Alzheimer’s disease: it’s all about context. Int J Alzheimers Dis 2012:314185. doi:10.1155/2012/314185

    PubMed  Google Scholar 

  31. Green KN, LaFerla FM (2008) Linking calcium to Abeta and Alzheimer’s disease. Neuron 59(2):190–194. doi:10.1016/j.neuron.2008.07.013

    PubMed  CAS  Google Scholar 

  32. Moreira PI, Honda K, Liu Q, Santos MS, Oliveira CR, Aliev G, Nunomura A, Zhu X, Smith MA, Perry G (2005) Oxidative stress: the old enemy in Alzheimer’s disease pathophysiology. Curr Alzheimer Res 2(4):403–408

    PubMed  CAS  Google Scholar 

  33. Querfurth HW, LaFerla FM (2010) Alzheimer’s disease. N Engl J Med 362(4):329–344. doi:10.1056/NEJMra0909142

    PubMed  CAS  Google Scholar 

  34. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8(7):519–529. doi:10.1038/nrm2199

    PubMed  CAS  Google Scholar 

  35. Walter P, Ron D (2011) The unfolded protein response: from stress pathway to homeostatic regulation. Science 334(6059):1081–1086. doi:10.1126/science.1209038

    PubMed  CAS  Google Scholar 

  36. Tabas I, Ron D (2011) Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol 13(3):184–190. doi:10.1038/ncb0311-184

    PubMed  CAS  Google Scholar 

  37. Hetz C, Glimcher LH (2009) Fine-tuning of the unfolded protein response: assembling the IRE1alpha interactome. Mol Cell 35(5):551–561. doi:10.1016/j.molcel.2009.08.021

    PubMed  CAS  Google Scholar 

  38. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, Clark SG, Ron D (2002) IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 415(6867):92–96. doi:10.1038/415092a

    PubMed  CAS  Google Scholar 

  39. Lee K, Tirasophon W, Shen X, Michalak M, Prywes R, Okada T, Yoshida H, Mori K, Kaufman RJ (2002) IRE1-mediated unconventional mRNA splicing and S2P-mediated ATF6 cleavage merge to regulate XBP1 in signaling the unfolded protein response. Genes Dev 16(4):452–466. doi:10.1101/gad.964702

    PubMed  CAS  Google Scholar 

  40. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K (2001) XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 107(7):881–891

    PubMed  CAS  Google Scholar 

  41. Lee AH, Iwakoshi NN, Glimcher LH (2003) XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol Cell Biol 23(21):7448–7459

    PubMed  CAS  Google Scholar 

  42. Acosta-Alvear D, Zhou Y, Blais A, Tsikitis M, Lents NH, Arias C, Lennon CJ, Kluger Y, Dynlacht BD (2007) XBP1 controls diverse cell type- and condition-specific transcriptional regulatory networks. Mol Cell 27(1):53–66. doi:10.1016/j.molcel.2007.06.011

    PubMed  CAS  Google Scholar 

  43. Hetz C, Martinon F, Rodriguez D, Glimcher LH (2011) The unfolded protein response: integrating stress signals through the stress sensor IRE1alpha. Physiol Rev 91(4):1219–1243. doi:10.1152/physrev.00001.2011

    PubMed  CAS  Google Scholar 

  44. Han D, Lerner AG, Vande Walle L, Upton JP, Xu W, Hagen A, Backes BJ, Oakes SA, Papa FR (2009) IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell 138(3):562–575. doi:10.1016/j.cell.2009.07.017

    PubMed  CAS  Google Scholar 

  45. Hollien J, Lin JH, Li H, Stevens N, Walter P, Weissman JS (2009) Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. J Cell Biol 186(3):323–331. doi:10.1083/jcb.200903014

    PubMed  CAS  Google Scholar 

  46. Hollien J, Weissman JS (2006) Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Science 313(5783):104–107. doi:10.1126/science.1129631

    PubMed  CAS  Google Scholar 

  47. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6(5):1099–1108

    PubMed  CAS  Google Scholar 

  48. Schroder M, Kaufman RJ (2005) The mammalian unfolded protein response. Annu Rev Biochem 74:739–789. doi:10.1146/annurev.biochem.73.011303.074134

    PubMed  Google Scholar 

  49. Yamamoto K, Sato T, Matsui T, Sato M, Okada T, Yoshida H, Harada A, Mori K (2007) Transcriptional induction of mammalian ER quality control proteins is mediated by single or combined action of ATF6alpha and XBP1. Dev cell 13(3):365–376. doi:10.1016/j.devcel.2007.07.018

    PubMed  CAS  Google Scholar 

  50. Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12(7):982–995

    PubMed  CAS  Google Scholar 

  51. Shore GC, Papa FR, Oakes SA (2011) Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol 23:143–149

    Google Scholar 

  52. Woehlbier U, Hetz C (2011) Modulating stress responses by the UPRosome: a matter of life and death. Trends Biochem Sci 36(6):329–337. doi:10.1016/j.tibs.2011.03.001

    PubMed  CAS  Google Scholar 

  53. Shore GC, Papa FR, Oakes SA (2011) Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol 23(2):143–149. doi:10.1016/j.ceb.2010.11.003

    PubMed  CAS  Google Scholar 

  54. Lee JH, Won SM, Suh J, Son SJ, Moon GJ, Park UJ, Gwag BJ (2010) Induction of the unfolded protein response and cell death pathway in Alzheimer’s disease, but not in aged Tg2576 mice. Exp Mol Med 42(5):386–394

    PubMed  CAS  Google Scholar 

  55. Hoozemans JJ, Stieler J, van Haastert ES, Veerhuis R, Rozemuller AJ, Baas F, Eikelenboom P, Arendt T, Scheper W (2006) The unfolded protein response affects neuronal cell cycle protein expression: implications for Alzheimer’s disease pathogenesis. Exp Gerontol 41(4):380–386. doi:10.1016/j.exger.2006.01.013

    PubMed  CAS  Google Scholar 

  56. Kaneko M, Koike H, Saito R, Kitamura Y, Okuma Y, Nomura Y (2010) Loss of HRD1-mediated protein degradation causes amyloid precursor protein accumulation and amyloid-beta generation. J Neurosci 30(11):3924–3932. doi:10.1523/JNEUROSCI.2422-09.2010

    PubMed  CAS  Google Scholar 

  57. Scheper W, Hoozemans JJ, Hoogenraad CC, Rozemuller AJ, Eikelenboom P, Baas F (2007) Rab6 is increased in Alzheimer’s disease brain and correlates with endoplasmic reticulum stress. Neuropathol Appl Neurobiol 33(5):523–532. doi:10.1111/j.1365-2990.2007.00846.x

    PubMed  CAS  Google Scholar 

  58. Hoozemans JJ, Veerhuis R, Van Haastert ES, Rozemuller JM, Baas F, Eikelenboom P, Scheper W (2005) The unfolded protein response is activated in Alzheimer’s disease. Acta Neuropathol 110(2):165–172. doi:10.1007/s00401-005-1038-0

    PubMed  CAS  Google Scholar 

  59. Hamos JE, Oblas B, Pulaski-Salo D, Welch WJ, Bole DG, Drachman DA (1991) Expression of heat shock proteins in Alzheimer’s disease. Neurology 41(3):345–350

    PubMed  CAS  Google Scholar 

  60. Kudo T, Okumura M, Imaizumi K, Araki W, Morihara T, Tanimukai H, Kamagata E, Tabuchi N, Kimura R, Kanayama D, Fukumori A, Tagami S, Okochi M, Kubo M, Tanii H, Tohyama M, Tabira T, Takeda M (2006) Altered localization of amyloid precursor protein under endoplasmic reticulum stress. Biochem Biophys Res Commun 344(2):525–530. doi:10.1016/j.bbrc.2006.03.173

    PubMed  CAS  Google Scholar 

  61. Honjo Y, Ito H, Horibe T, Takahashi R, Kawakami K (2010) Protein disulfide isomerase-immunopositive inclusions in patients with Alzheimer disease. Brain Res 1349:90–96. doi:10.1016/j.brainres.2010.06.016

    PubMed  CAS  Google Scholar 

  62. Biswas SC, Shi Y, Vonsattel JP, Leung CL, Troy CM, Greene LA (2007) Bim is elevated in Alzheimer’s disease neurons and is required for beta-amyloid-induced neuronal apoptosis. J Neurosci 27(4):893–900. doi:10.1523/JNEUROSCI.3524-06.2007

    PubMed  CAS  Google Scholar 

  63. Sai X, Kawamura Y, Kokame K, Yamaguchi H, Shiraishi H, Suzuki R, Suzuki T, Kawaichi M, Miyata T, Kitamura T, De Strooper B, Yanagisawa K, Komano H (2002) Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-mediated generation of amyloid beta-protein. J Biol Chem 277(15):12915–12920. doi:10.1074/jbc.M112372200

    PubMed  CAS  Google Scholar 

  64. O'Connor T, Sadleir KR, Maus E, Velliquette RA, Zhao J, Cole SL, Eimer WA, Hitt B, Bembinster LA, Lammich S, Lichtenthaler SF, Hebert SS, De Strooper B, Haass C, Bennett DA, Vassar R (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60(6):988–1009. doi:10.1016/j.neuron.2008.10.047

    PubMed  Google Scholar 

  65. Nijholt DA, de Graaf TR, van Haastert ES, Oliveira AO, Berkers CR, Zwart R, Ovaa H, Baas F, Hoozemans JJ, Scheper W (2011) Endoplasmic reticulum stress activates autophagy but not the proteasome in neuronal cells: implications for Alzheimer’s disease. Cell Death Differ 18(6):1071–1081. doi:10.1038/cdd.2010.176

    PubMed  CAS  Google Scholar 

  66. Hoozemans JJ, van Haastert ES, Nijholt DA, Rozemuller AJ, Eikelenboom P, Scheper W (2009) The unfolded protein response is activated in pretangle neurons in Alzheimer’s disease hippocampus. Am J Pathol 174(4):1241–1251. doi:10.2353/ajpath.2009.080814

    PubMed  CAS  Google Scholar 

  67. Chang RC, Wong AK, Ng HK, Hugon J (2002) Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer’s disease. Neuroreport 13(18):2429–2432. doi:10.1097/01.wnr.0000048020.74602.bb

    PubMed  CAS  Google Scholar 

  68. Onuki R, Bando Y, Suyama E, Katayama T, Kawasaki H, Baba T, Tohyama M, Taira K (2004) An RNA-dependent protein kinase is involved in tunicamycin-induced apoptosis and Alzheimer’s disease. EMBO J 23(4):959–968. doi:10.1038/sj.emboj.7600049

    PubMed  CAS  Google Scholar 

  69. Hoozemans JJ, Scheper W (2012) Endoplasmic reticulum: the unfolded protein response is tangled in neurodegeneration. Int J Biochem Cell Biol 44(8):1295–1298. doi:10.1016/j.biocel.2012.04.023

    PubMed  CAS  Google Scholar 

  70. Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2011) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol. doi:10.1002/path.3969

    Google Scholar 

  71. Resende R, Ferreiro E, Pereira C, Oliveira CR (2008) ER stress is involved in Aβ–induced GSK–3β activation and tau phosphorylation. J Neurosci Res 86(9):2091–2099. doi:10.1002/jnr.21648

    PubMed  CAS  Google Scholar 

  72. Ferreiro E, Pereira CM (2011) Endoplasmic reticulum stress: a new playER in tauopathies. J Pathol. doi:10.1002/path.3977

    Google Scholar 

  73. Sakagami Y, Kudo T, Tanimukai H, Kanayama D, Omi T, Horiguchi K, Okochi M, Imaizumi K, Takeda M (2013) Involvement of endoplasmic reticulum stress in tauopathy. Biochem Biophys Res Commun 430(2):500–504. doi:10.1016/j.bbrc.2012.12.007

    PubMed  CAS  Google Scholar 

  74. Park YJ, Jang YM, Kwon YH (2009) Isoflavones prevent endoplasmic reticulum stress-mediated neuronal degeneration by inhibiting tau hyperphosphorylation in SH-SY5Y cells. J Med Food 12(3):528–535. doi:10.1089/jmf.2008.1069

    PubMed  CAS  Google Scholar 

  75. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PM, Wang LS, Klei L, Rademakers R, de Silva R, Litvan I, Riley DE, van Swieten JC, Heutink P, Wszolek ZK, Uitti RJ, Vandrovcova J, Hurtig HI, Gross RG, Maetzler W, Goldwurm S, Tolosa E, Borroni B, Pastor P, Cantwell LB, Han MR, Dillman A, van der Brug MP, Gibbs JR, Cookson MR, Hernandez DG, Singleton AB, Farrer MJ, Yu CE, Golbe LI, Revesz T, Hardy J, Lees AJ, Devlin B, Hakonarson H, Muller U, Schellenberg GD (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43(7):699–705. doi:10.1038/ng.859

    PubMed  Google Scholar 

  76. Loewen CA, Feany MB (2010) The unfolded protein response protects from tau neurotoxicity in vivo. PLoS One 5 (9). doi:10.1371/journal.pone.0013084

  77. Mattson MP, Guo Q, Furukawa K, Pedersen WA (1998) Presenilins, the endoplasmic reticulum, and neuronal apoptosis in Alzheimer’s disease. J Neurochem 70(1):1–14

    PubMed  CAS  Google Scholar 

  78. Niwa M, Sidrauski C, Kaufman RJ, Walter P (1999) A role for presenilin-1 in nuclear accumulation of Ire1 fragments and induction of the mammalian unfolded protein response. Cell 99(7):691–702

    PubMed  CAS  Google Scholar 

  79. Katayama T, Imaizumi K, Sato N, Miyoshi K, Kudo T, Hitomi J, Morihara T, Yoneda T, Gomi F, Mori Y, Nakano Y, Takeda J, Tsuda T, Itoyama Y, Murayama O, Takashima A, St George-Hyslop P, Takeda M, Tohyama M (1999) Presenilin-1 mutations downregulate the signalling pathway of the unfolded-protein response. Nat Cell Biol 1(8):479–485. doi:10.1038/70265

    PubMed  CAS  Google Scholar 

  80. Sato N, Urano F, Yoon Leem J, Kim SH, Li M, Donoviel D, Bernstein A, Lee AS, Ron D, Veselits ML, Sisodia SS, Thinakaran G (2000) Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression. Nat Cell Biol 2(12):863–870. doi:10.1038/35046500

    PubMed  CAS  Google Scholar 

  81. Piccini A, Fassio A, Pasqualetto E, Vitali A, Borghi R, Palmieri D, Nacmias B, Sorbi S, Sitia R, Tabaton M (2004) Fibroblasts from FAD-linked presenilin 1 mutations display a normal unfolded protein response but overproduce Abeta42 in response to tunicamycin. Neurobiol Dis 15(2):380–386. doi:10.1016/j.nbd.2003.11.013

    PubMed  CAS  Google Scholar 

  82. Yasuda Y, Kudo T, Katayama T, Imaizumi K, Yatera M, Okochi M, Yamamori H, Matsumoto N, Kida T, Fukumori A, Okumura M, Tohyama M, Takeda M (2002) FAD-linked presenilin-1 mutants impede translation regulation under ER stress. Biochem Biophys Res Commun 296(2):313–318

    PubMed  CAS  Google Scholar 

  83. Terro F, Czech C, Esclaire F, Elyaman W, Yardin C, Baclet MC, Touchet N, Tremp G, Pradier L, Hugon J (2002) Neurons overexpressing mutant presenilin-1 are more sensitive to apoptosis induced by endoplasmic reticulum-Golgi stress. J Neurosci Res 69(4):530–539. doi:10.1002/jnr.10312

    PubMed  CAS  Google Scholar 

  84. Katayama T, Imaizumi K, Honda A, Yoneda T, Kudo T, Takeda M, Mori K, Rozmahel R, Fraser P, George-Hyslop PS, Tohyama M (2001) Disturbed activation of endoplasmic reticulum stress transducers by familial Alzheimer’s disease-linked presenilin-1 mutations. J Biol Chem 276(46):43446–43454. doi:10.1074/jbc.M104096200

    PubMed  CAS  Google Scholar 

  85. Yang Y, Turner RS, Gaut JR (1998) The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion. J Biol Chem 273(40):25552–25555

    PubMed  CAS  Google Scholar 

  86. Jin H, Sanjo N, Uchihara T, Watabe K, St George-Hyslop P, Fraser PE, Mizusawa H (2010) Presenilin-1 holoprotein is an interacting partner of sarco endoplasmic reticulum calcium-ATPase and confers resistance to endoplasmic reticulum stress. J Alzheimers Dis 20(1):261–273. doi:10.3233/JAD-2010-1360

    PubMed  CAS  Google Scholar 

  87. Yukioka F, Matsuzaki S, Kawamoto K, Koyama Y, Hitomi J, Katayama T, Tohyama M (2008) Presenilin-1 mutation activates the signaling pathway of caspase-4 in endoplasmic reticulum stress-induced apoptosis. Neurochem Int 52(4–5):683–687. doi:10.1016/j.neuint.2007.08.017

    PubMed  CAS  Google Scholar 

  88. Honarnejad K, Herms J (2012) Presenilins: role in calcium homeostasis. Int J Biochem Cell Biol 44(11):1983–1986. doi:10.1016/j.biocel.2012.07.019

    PubMed  CAS  Google Scholar 

  89. Woods NK, Padmanabhan J (2012) Neuronal calcium signaling and Alzheimer’s disease. Adv Exp Med Biol 740:1193–1217. doi:10.1007/978-94-007-2888-2_54

    PubMed  CAS  Google Scholar 

  90. Katayama T, Imaizumi K, Manabe T, Hitomi J, Kudo T, Tohyama M (2004) Induction of neuronal death by ER stress in Alzheimer’s disease. J Chem Neuroanat 28(1–2):67–78. doi:10.1016/j.jchemneu.2003.12.004

    PubMed  CAS  Google Scholar 

  91. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765):98–103. doi:10.1038/47513

    PubMed  CAS  Google Scholar 

  92. Quiroz-Baez R, Ferrera P, Rosendo-Gutierrez R, Moran J, Bermudez-Rattoni F, Arias C (2011) Caspase-12 activation is involved in amyloid-beta protein-induced synaptic toxicity. J Alzheimers Dis 26(3):467–476. doi:10.3233/JAD-2011-110326

    PubMed  CAS  Google Scholar 

  93. Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol 165(3):347–356. doi:10.1083/jcb.200310015

    PubMed  CAS  Google Scholar 

  94. Costa RO, Lacor PN, Ferreira IL, Resende R, Auberson YP, Klein WL, Oliveira CR, Rego AC, Pereira CM (2012) Endoplasmic reticulum stress occurs downstream of GluN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-beta oligomers. Aging Cell 11(5):823–833. doi:10.1111/j.1474-9726.2012.00848.x

    PubMed  CAS  Google Scholar 

  95. Nishitsuji K, Tomiyama T, Ishibashi K, Ito K, Teraoka R, Lambert MP, Klein WL, Mori H (2009) The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells. Am J Pathol 174(3):957–969. doi:10.2353/ajpath.2009.080480

    PubMed  CAS  Google Scholar 

  96. Imai T, Kosuge Y, Ishige K, Ito Y (2007) Amyloid beta-protein potentiates tunicamycin-induced neuronal death in organotypic hippocampal slice cultures. Neuroscience 147(3):639–651. doi:10.1016/j.neuroscience.2007.04.057

    PubMed  CAS  Google Scholar 

  97. Chafekar SM, Zwart R, Veerhuis R, Vanderstichele H, Baas F, Scheper W (2008) Increased Abeta1-42 production sensitizes neuroblastoma cells for ER stress toxicity. Curr Alzheimer Res 5(5):469–474

    PubMed  CAS  Google Scholar 

  98. Seyb KI, Ansar S, Bean J, Michaelis ML (2006) Beta-amyloid and endoplasmic reticulum stress responses in primary neurons: effects of drugs that interact with the cytoskeleton. J Mol Neurosci 28(2):111–123

    PubMed  CAS  Google Scholar 

  99. Ferreiro E, Resende R, Costa R, Oliveira CR, Pereira CM (2006) An endoplasmic-reticulum-specific apoptotic pathway is involved in prion and amyloid-beta peptides neurotoxicity. Neurobiol Dis 23(3):669–678. doi:10.1016/j.nbd.2006.05.011

    PubMed  CAS  Google Scholar 

  100. Kosuge Y, Sakikubo T, Ishige K, Ito Y (2006) Comparative study of endoplasmic reticulum stress-induced neuronal death in rat cultured hippocampal and cerebellar granule neurons. Neurochem Int 49(3):285–293. doi:10.1016/j.neuint.2006.01.021

    PubMed  CAS  Google Scholar 

  101. Casas-Tinto S, Zhang Y, Sanchez-Garcia J, Gomez-Velazquez M, Rincon-Limas DE, Fernandez-Funez P (2011) The ER stress factor XBP1s prevents amyloid-beta neurotoxicity. Hum Mol Genet 20(11):2144–2160. doi:10.1093/hmg/ddr100

    PubMed  CAS  Google Scholar 

  102. Castillo-Carranza DL, Zhang Y, Guerrero-Munoz MJ, Kayed R, Rincon-Limas DE, Fernandez-Funez P (2012) Differential activation of the ER stress factor XBP1 by oligomeric assemblies. Neurochem Res 37(8):1707–1717. doi:10.1007/s11064-012-0780-7

    PubMed  CAS  Google Scholar 

  103. Alberdi E, Wyssenbach A, Alberdi M, Sanchez-Gomez MV, Cavaliere F, Rodriguez JJ, Verkhratsky A, Matute C (2013) Ca(2+)-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid beta-treated astrocytes and in a model of Alzheimer’s disease. Aging Cell. doi:10.1111/acel.12054

    PubMed  Google Scholar 

  104. Lai CS, Preisler J, Baum L, Lee DH, Ng HK, Hugon J, So KF, Chang RC (2009) Low molecular weight Abeta induces collapse of endoplasmic reticulum. Mol Cell Neurosci 41(1):32–43. doi:10.1016/j.mcn.2009.01.006

    PubMed  CAS  Google Scholar 

  105. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno SI, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein WL, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H (2013) Modeling Alzheimer’s disease with iPSCs reveals stress phenotypes associated with intracellular abeta and differential drug responsiveness. Cell Stem Cell. doi:10.1016/j.stem.2013.01.009

    PubMed  Google Scholar 

  106. Costa RO, Ferreiro E, Cardoso SM, Oliveira CR, Pereira CM (2010) ER stress-mediated apoptotic pathway induced by Abeta peptide requires the presence of functional mitochondria. J Alzheimers Dis 20(2):625–636. doi:10.3233/JAD-2010-091369

    PubMed  CAS  Google Scholar 

  107. Costa RO, Ferreiro E, Martins I, Santana I, Cardoso SM, Oliveira CR, Pereira CM (2012) Amyloid beta-induced ER stress is enhanced under mitochondrial dysfunction conditions. Neurobiol Aging 33(4):824.e5–824.e16. doi:10.1016/j.neurobiolaging.2011.04.011

    CAS  Google Scholar 

  108. Costa RO, Ferreiro E, Oliveira CR, Pereira CM (2012) Inhibition of mitochondrial cytochrome c oxidase potentiates Abeta-induced ER stress and cell death in cortical neurons. Mol Cell Neurosci. doi:10.1016/j.mcn.2012.09.005

    Google Scholar 

  109. Ferreiro E, Baldeiras I, Ferreira IL, Costa RO, Rego AC, Pereira CF, Oliveira CR (2012) Mitochondrial- and endoplasmic reticulum-associated oxidative stress in Alzheimer’s disease: from pathogenesis to biomarkers. Int J Cell Biol 2012:735206. doi:10.1155/2012/735206

    PubMed  CAS  Google Scholar 

  110. Viana RJ, Nunes AF, Rodrigues CM (2012) Endoplasmic reticulum enrollment in Alzheimer’s disease. Mol Neurobiol. doi:10.1007/s12035-012-8301-x

    Google Scholar 

  111. Yu MS, Suen KC, Kwok NS, So KF, Hugon J, Chang RC (2006) Beta-amyloid peptides induces neuronal apoptosis via a mechanism independent of unfolded protein responses. Apoptosis 11(5):687–700. doi:10.1007/s10495-006-5540-1

    PubMed  CAS  Google Scholar 

  112. Chafekar SM, Hoozemans JJ, Zwart R, Baas F, Scheper W (2007) Abeta 1-42 induces mild endoplasmic reticulum stress in an aggregation state-dependent manner. Antioxid Redox Signal 9(12):2245–2254. doi:10.1089/ars.2007.1797

    PubMed  CAS  Google Scholar 

  113. Lee do Y, Lee KS, Lee HJ, Kim do H, Noh YH, Yu K, Jung HY, Lee SH, Lee JY, Youn YC, Jeong Y, Kim DK, Lee WB, Kim SS (2010) Activation of PERK signaling attenuates Abeta-mediated ER stress. PLoS One 5(5):e10489. doi:10.1371/journal.pone.0010489

    PubMed  Google Scholar 

  114. Ghribi O, Herman MM, Pramoonjago P, Spaulding NK, Savory J (2004) GDNF regulates the A beta-induced endoplasmic reticulum stress response in rabbit hippocampus by inhibiting the activation of gadd 153 and the JNK and ERK kinases. Neurobiol Dis 16(2):417–427. doi:10.1016/j.nbd.2004.04.002

    PubMed  CAS  Google Scholar 

  115. Ricobaraza A, Cuadrado-Tejedor M, Marco S, Perez-Otano I, Garcia-Osta A (2012) Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease. Hippocampus 22(5):1040–1050. doi:10.1002/hipo.20883

    PubMed  CAS  Google Scholar 

  116. Yoon SO, Park DJ, Ryu JC, Ozer HG, Tep C, Shin YJ, Lim TH, Pastorino L, Kunwar AJ, Walton JC, Nagahara AH, Lu KP, Nelson RJ, Tuszynski MH, Huang K (2012) JNK3 perpetuates metabolic stress induced by Abeta peptides. Neuron 75(5):824–837. doi:10.1016/j.neuron.2012.06.024

    PubMed  CAS  Google Scholar 

  117. Pannaccione A, Secondo A, Molinaro P, D'Avanzo C, Cantile M, Esposito A, Boscia F, Scorziello A, Sirabella R, Di Renzo G, Annunziato L (2012) A new concept: Abeta1-42 generates a hyperfunctional proteolytic NCX3 fragment that delays caspase-12 activation and neuronal death. J Neurosci 32(31):10609–10617. doi:10.1523/JNEUROSCI.6429-11.2012

    PubMed  CAS  Google Scholar 

  118. Takahashi K, Niidome T, Akaike A, Kihara T, Sugimoto H (2009) Amyloid precursor protein promotes endoplasmic reticulum stress-induced cell death via C/EBP homologous protein-mediated pathway. J Neurochem 109(5):1324–1337. doi:10.1111/j.1471-4159.2009.06067.x

    PubMed  CAS  Google Scholar 

  119. Kogel D, Concannon CG, Muller T, Konig H, Bonner C, Poeschel S, Chang S, Egensperger R, Prehn JH (2011) The APP intracellular domain (AICD) potentiates ER stress-induced apoptosis. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2011.06.012

    PubMed  Google Scholar 

  120. Mitsuda T, Hayakawa Y, Itoh M, Ohta K, Nakagawa T (2007) ATF4 regulates gamma-secretase activity during amino acid imbalance. Biochem Biophys Res Commun 352(3):722–727. doi:10.1016/j.bbrc.2006.11.075

    PubMed  CAS  Google Scholar 

  121. Ohta K, Mizuno A, Li S, Itoh M, Ueda M, Ohta E, Hida Y, Wang MX, Furoi M, Tsuzuki Y, Sobajima M, Bohmoto Y, Fukushima T, Kobori M, Inuzuka T, Nakagawa T (2011) Endoplasmic reticulum stress enhances gamma-secretase activity. Biochem Biophys Res Commun 416(3–4):362–366. doi:10.1016/j.bbrc.2011.11.042

    PubMed  CAS  Google Scholar 

  122. Domingues SCTS, Henriques AG, Wu W, Da Cruz e Silva EF, Da Cruz e Silva OAB (2007) Altered subcellular distribution of the Alzheimer’s amyloid precursor protein under stress conditions. Ann N Y Acad Sci 1096:184–195. doi:10.1196/annals.1397.085

    PubMed  CAS  Google Scholar 

  123. Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM, Doms RW (1997) Alzheimer’s A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med 3(9):1021–1023

    PubMed  CAS  Google Scholar 

  124. Hare JF (2006) Intracellular pathways of folded and misfolded amyloid precursor protein degradation. Arch Biochem Biophys 451(1):79–90. doi:10.1016/j.abb.2006.05.002

    PubMed  CAS  Google Scholar 

  125. Cheung ZH. Ip NY Cdk5: a multifaceted kinase in neurodegenerative diseases. Trends Cell Biol 22(3):169–175. doi:10.1016/j.tcb.2011.11.003

  126. Saito T, Konno T, Hosokawa T, Asada A, Ishiguro K, Hisanaga S (2007) p25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons. J Neurochem 102(1):133–140. doi:10.1111/j.1471-4159.2007.04540.x

    PubMed  CAS  Google Scholar 

  127. Andreu CI, Woehlbier U, Torres M, Hetz C (2012) Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications. FEBS Lett 586(18):2826–2834. doi:10.1016/j.febslet.2012.07.023

    PubMed  CAS  Google Scholar 

  128. Uehara T, Nakamura T, Yao D, Shi ZQ, Gu Z, Ma Y, Masliah E, Nomura Y, Lipton SA (2006) S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 441(7092):513–517. doi:10.1038/nature04782

    PubMed  CAS  Google Scholar 

  129. Hoffstrom BG, Kaplan A, Letso R, Schmid RS, Turmel GJ, Lo DC, Stockwell BR (2010) Inhibitors of protein disulfide isomerase suppress apoptosis induced by misfolded proteins. Nature Chemical Biology:1–7. doi:10.1038/nchembio.467

  130. Liu SY, Wang W, Cai ZY, Yao LF, Chen ZW, Wang CY, Zhao B, Li KS (2013) Polymorphism −116C/G of human X-box-binding protein 1 promoter is associated with risk of Alzheimer’s disease. CNS Neurosci Ther. doi:10.1111/cns.12064

    Google Scholar 

  131. Kakiuchi C, Iwamoto K, Ishiwata M, Bundo M, Kasahara T, Kusumi I, Tsujita T, Okazaki Y, Nanko S, Kunugi H, Sasaki T, Kato T (2003) Impaired feedback regulation of XBP1 as a genetic risk factor for bipolar disorder. Nat Genet 35(2):171–175. doi:10.1038/ng1235

    PubMed  CAS  Google Scholar 

  132. Watanabe Y, Fukui N, Muratake T, Amagane H, Kaneko N, Nunokawa A, Someya T (2006) Association study of a functional promoter polymorphism of the X-box binding protein 1 gene in Japanese patients with schizophrenia. Psychiatr Clin Neurosci 60(5):633–635. doi:10.1111/j.1440-1819.2006.01570.x

    CAS  Google Scholar 

  133. Kusumi I, Masui T, Kakiuchi C, Suzuki K, Akimoto T, Hashimoto R, Kunugi H, Kato T, Koyama T (2005) Relationship between XBP1 genotype and personality traits assessed by TCI and NEO-FFI. Neurosci Lett 391(1–2):7–10. doi:10.1016/j.neulet.2005.08.023

    PubMed  CAS  Google Scholar 

  134. Hou SJ, Yen FC, Cheng CY, Tsai SJ, Hong CJ (2004) X-box binding protein 1 (XBP1) C–116G polymorphisms in bipolar disorders and age of onset. Neurosci Lett 367(2):232–234. doi:10.1016/j.neulet.2004.06.012

    PubMed  CAS  Google Scholar 

  135. Cichon S, Buervenich S, Kirov G, Akula N, Dimitrova A, Green E, Schumacher J, Klopp N, Becker T, Ohlraun S, Schulze TG, Tullius M, Gross MM, Jones L, Krastev S, Nikolov I, Hamshere M, Jones I, Czerski PM, Leszczynska-Rodziewicz A, Kapelski P, Bogaert AV, Illig T, Hauser J, Maier W, Berrettini W, Byerley W, Coryell W, Gershon ES, Kelsoe JR, McInnis MG, Murphy DL, Nurnberger JI, Reich T, Scheftner W, O'Donovan MC, Propping P, Owen MJ, Rietschel M, Nothen MM, McMahon FJ, Craddock N (2004) Lack of support for a genetic association of the XBP1 promoter polymorphism with bipolar disorder in probands of European origin. Nat Genet 36(8):783–784. doi:10.1038/ng0804-783, author reply 784–785

    PubMed  CAS  Google Scholar 

  136. Chen A, Muzzio IA, Malleret G, Bartsch D, Verbitsky M, Pavlidis P, Yonan AL, Vronskaya S, Grody MB, Cepeda I, Gilliam TC, Kandel ER (2003) Inducible enhancement of memory storage and synaptic plasticity in transgenic mice expressing an inhibitor of ATF4 (CREB-2) and C/EBP proteins. Neuron 39(4):655–669

    PubMed  CAS  Google Scholar 

  137. Costa-Mattioli M, Gobert D, Harding H, Herdy B, Azzi M, Bruno M, Bidinosti M, Ben Mamou C, Marcinkiewicz E, Yoshida M, Imataka H, Cuello AC, Seidah N, Sossin W, Lacaille JC, Ron D, Nader K, Sonenberg N (2005) Translational control of hippocampal synaptic plasticity and memory by the eIF2alpha kinase GCN2. Nature 436(7054):1166–1173. doi:10.1038/nature03897

    PubMed  CAS  Google Scholar 

  138. Costa-Mattioli M, Gobert D, Stern E, Gamache K, Colina R, Cuello C, Sossin W, Kaufman R, Pelletier J, Rosenblum K, Krnjevic K, Lacaille JC, Nader K, Sonenberg N (2007) eIF2alpha phosphorylation bidirectionally regulates the switch from short- to long-term synaptic plasticity and memory. Cell 129(1):195–206. doi:10.1016/j.cell.2007.01.050

    PubMed  CAS  Google Scholar 

  139. Valenzuela V, Collyer E, Armentano D, Parsons GB, Court FA, Hetz C (2012) Activation of the unfolded protein response enhances motor recovery after spinal cord injury. Cell Death Dis 3:e272. doi:10.1038/cddis.2012.8

    PubMed  CAS  Google Scholar 

  140. Kraskiewicz H, FitzGerald U (2012) InterfERing with endoplasmic reticulum stress. Trends Pharmacol Sci 33(2):53–63. doi:10.1016/j.tips.2011.10.002

    PubMed  CAS  Google Scholar 

  141. Erickson RR, Dunning LM, Olson DA, Cohen SJ, Davis AT, Wood WG, Kratzke RA, Holtzman JL (2005) In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind beta-amyloid. Biochem Biophys Res Commun 332(1):50–57. doi:10.1016/j.bbrc.2005.04.090

    PubMed  CAS  Google Scholar 

  142. Tohda C, Urano T, Umezaki M, Nemere I, Kuboyama T (2012) Diosgenin is an exogenous activator of 1,25D(3)-MARRS/Pdia3/ERp57 and improves Alzheimer’s disease pathologies in 5XFAD mice. Sci Rep 2:535. doi:10.1038/srep00535

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to Drs. Andrea Paula-Lima, Ute Woehlbier, and René Vidal for critical comments on the manuscript. This work was primary funded by the Alzheimer’s Association and Millennium Institute No. P09-015-F. We also received support from the Muscular Dystrophy Association, ALS Therapy Alliance, FONDECYT No. 1100176, Ring Initiative Act 1109, FONDEF D11I1007 and the Michael J. Fox Foundation for Parkinson Research (to C.H.), and CONICYT Ph.D. fellowship (to V.H.C.).

Author information

Authors and Affiliations

  1. Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile

    Víctor Hugo Cornejo & Claudio Hetz

  2. Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile

    Víctor Hugo Cornejo & Claudio Hetz

  3. Neurounion Biomedical Foundation, Santiago, Chile

    Claudio Hetz

  4. Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, USA

    Claudio Hetz

  5. Cellular and Molecular Biology Program, Institute of Biomedical Sciences, University of Chile, Independencia 1027, Santiago, Chile, P.O. BOX 70086

    Claudio Hetz

Authors
  1. Víctor Hugo Cornejo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Claudio Hetz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudio Hetz.

Additional information

This article is a contribution to the special issue on “The unfolded protein response in immune diseases” - Guest Editors: Richard Blumberg and Arthur Kaser

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cornejo, V.H., Hetz, C. The unfolded protein response in Alzheimer’s disease. Semin Immunopathol 35, 277–292 (2013). https://doi.org/10.1007/s00281-013-0373-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00281-013-0373-9

Keywords

Search

Navigation