Skip to main content

Advertisement

SpringerLink
Log in

Endoplasmic Reticulum Dysfunction in Alzheimer’s Disease

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The endoplasmic reticulum (ER) serves many crucial cellular functions. However, when misfolded or unfolded proteins accumulated in the ER, the stress of ER will be induced. Meanwhile, the intracellular signaling network, which is called unfolded protein response, will also be activated to cope with. Those unfolded proteins can be recognized by three kinds of stress sensors which are IRE1, PERK, and ATF6. Based on lots of medical reports, ER stress in postmortem brains from Alzheimer’s disease (AD) patients, animals, and vitro models have indicated that ER dysfunction might work as an important part in causing AD. In this review, we demonstrated that the effect of ER stress contributed to the pathogenesis of AD. ER stress associates almost the whole brain pathology processes which can be observed in AD, such as gene mutation of presenilin1, the abnormal clipped mRNA of presenilin2, β-amyloid production, tau phosphorylation, and cell death. The status of ER stress and unfolded protein response in the pathogenesis of AD also suggests they can be used as potential therapeutic agents.

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

References

  1. 2011 Alzheimer’s disease facts and figures (2011) Alzheimer’s & dementia 7 (2):208-244 doi:10.1016/j.jalz.2011.02.004

  2. Jiang T, Yu JT, Tian Y, Tan L (2013) Epidemiology and etiology of Alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer’s Res 10(8):852–867

    Article  CAS  Google Scholar 

  3. Jiang T, Yu JT, Tan L (2012) Novel disease-modifying therapies for Alzheimer’s disease. J Alzheimer’s Dis JAD 31(3):475–492. doi:10.3233/JAD-2012-120640

    CAS  Google Scholar 

  4. Thomas PJ, Qu B-H, Pedersen PL (1995) Defective protein folding as a basis of human disease. Trends Biochem Sci 20(11):456–459. doi:10.1016/S0968-0004(00)89100-8

    Article  CAS  PubMed  Google Scholar 

  5. 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

    Article  CAS  PubMed  Google Scholar 

  6. Smith MH, Ploegh HL, Weissman JS (2011) Road to ruin: targeting proteins for degradation in the endoplasmic reticulum. Science 334(6059):1086–1090. doi:10.1126/science.1209235

    Article  CAS  PubMed  Google Scholar 

  7. Haas IG, Wabl M (1983) Immunoglobulin heavy chain binding protein. Nature 306(5941):387–389

    Article  CAS  PubMed  Google Scholar 

  8. Sanderson TH, Deogracias MP, Nangia KK, Wang J, Krause GS, Kumar R (2010) PKR-like endoplasmic reticulum kinase (PERK) activation following brain ischemia is independent of unfolded nascent proteins. Neuroscience 169(3):1307–1314. doi:10.1016/j.neuroscience.2010.05.076

    Article  CAS  PubMed  Google Scholar 

  9. Marciniak SJ, Garcia-Bonilla L, Hu J, Harding HP, Ron D (2006) Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol 172(2):201–209. doi:10.1083/jcb.200508099

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. 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

    Article  CAS  PubMed  Google Scholar 

  11. Park SW, Ozcan U (2013) Potential for therapeutic manipulation of the UPR in disease. Semin Immunopathol 35(3):351–373. doi:10.1007/s00281-013-0370-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA (2003) Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23(20):7198–7209

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Iwawaki T, Akai R, Yamanaka S, Kohno K (2009) Function of IRE1 alpha in the placenta is essential for placental development and embryonic viability. Proc Natl Acad Sci U S A 106(39):16657–16662. doi:10.1073/pnas.0903775106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Tsuru A, Fujimoto N, Takahashi S, Saito M, Nakamura D, Iwano M, Iwawaki T, Kadokura H, Ron D, Kohno K (2013) Negative feedback by IRE1beta optimizes mucin production in goblet cells. Proc Natl Acad Sci U S A 110(8):2864–2869. doi:10.1073/pnas.1212484110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. 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

    Article  CAS  PubMed  Google Scholar 

  16. Chen Y, Brandizzi F (2013) IRE1: ER stress sensor and cell fate executor. Trends Cell Biol 23(11):547–555. doi:10.1016/j.tcb.2013.06.005

    Article  CAS  PubMed  Google Scholar 

  17. Upton JP, Wang L, Han D, Wang ES, Huskey NE, Lim L, Truitt M, McManus MT, Ruggero D, Goga A, Papa FR, Oakes SA (2012) IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic Caspase-2. Science 338(6108):818–822. doi:10.1126/science.1226191

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Malhotra JD, Kaufman RJ (2007) The endoplasmic reticulum and the unfolded protein response. Semin Cell Dev Biol 18(6):716–731. doi:10.1016/j.semcdb.2007.09.003

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Ye J, Rawson RB, Komuro R, Chen X, Dave UP, Prywes R, Brown MS, Goldstein JL (2000) ER stress induces cleavage of membrane-bound ATF6 by the same proteases that process SREBPs. Mol Cell 6(6):1355–1364

    Article  CAS  PubMed  Google Scholar 

  21. Patil C, Walter P (2001) Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr Opin Cell Biol 13(3):349–355. doi:10.1016/S0955-0674(00)00219-2

    Article  CAS  PubMed  Google Scholar 

  22. 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

    Article  CAS  PubMed  Google Scholar 

  23. 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

    Article  PubMed Central  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. 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. doi:10.3858/emm.2010.42.5.040

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. 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

    Article  CAS  PubMed  Google Scholar 

  27. Kulczycki J, Bertrand E, Lojkowska W, Dowjat W, Wisniewski T, Lyczywek-Zwierz M (2001) Familial Alzheimer’s disease connected with mutation in presenilin gene 1 (P117L). Neurol Neurochir Pol 35(2):213–224

    CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. Milhavet O, Martindale JL, Camandola S, Chan SL, Gary DS, Cheng A, Holbrook NJ, Mattson MP (2002) Involvement of Gadd153 in the pathogenic action of presenilin-1 mutations. J Neurochem 83(3):673–681

    Article  CAS  PubMed  Google Scholar 

  30. Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14(9):1576–1582. doi:10.1038/sj.cdd.4402200

    Article  CAS  PubMed  Google Scholar 

  31. Nixon RA, Yang DS (2011) Autophagy failure in Alzheimer’s disease—locating the primary defect. Neurobiol Dis 43(1):38–45. doi:10.1016/j.nbd.2011.01.021

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Salminen A, Kaarniranta K (2009) Regulation of the aging process by autophagy. Trends Mol Med 15(5):217–224. doi:10.1016/j.molmed.2009.03.004

    Article  CAS  PubMed  Google Scholar 

  33. Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, St George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA (2011) Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer’s disease ameliorates amyloid pathologies and memory deficits. Brain J Neurol 134(Pt 1):258–277. doi:10.1093/brain/awq341

    Article  Google Scholar 

  34. Takuma K, Yan SS, Stern DM, Yamada K (2005) Mitochondrial dysfunction, endoplasmic reticulum stress, and apoptosis in Alzheimer’s disease. J Pharmacol Sci 97(3):312–316

    Article  CAS  PubMed  Google Scholar 

  35. Kishimoto Y, Kirino Y (2013) Presenilin 2 mutation accelerates the onset of impairment in trace eyeblink conditioning in a mouse model of Alzheimer’s disease overexpressing human mutant amyloid precursor protein. Neurosci Lett 538:15–19. doi:10.1016/j.neulet.2013.01.025

    Article  CAS  PubMed  Google Scholar 

  36. Sato N, Imaizumi K, Manabe T, Taniguchi M, Hitomi J, Katayama T, Yoneda T, Morihara T, Yasuda Y, Takagi T, Kudo T, Tsuda T, Itoyama Y, Makifuchi T, Fraser PE, St George-Hyslop P, Tohyama M (2001) Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. J Biol Chem 276(3):2108–2114. doi:10.1074/jbc.M006886200

    Article  CAS  PubMed  Google Scholar 

  37. Manabe T, Ohe K, Katayama T, Matsuzaki S, Yanagita T, Okuda H, Bando Y, Imaizumi K, Reeves R, Tohyama M, Mayeda A (2007) HMGA1a: sequence-specific RNA-binding factor causing sporadic Alzheimer’s disease-linked exon skipping of presenilin-2 pre-mRNA. Genes Cells Devoted Mol Cell Mech 12(10):1179–1191. doi:10.1111/j.1365-2443.2007.01123.x

    Article  CAS  Google Scholar 

  38. Manabe T, Katayama T, Sato N, Gomi F, Hitomi J, Yanagita T, Kudo T, Honda A, Mori Y, Matsuzaki S, Imaizumi K, Mayeda A, Tohyama M (2003) Induced HMGA1a expression causes aberrant splicing of Presenilin-2 pre-mRNA in sporadic Alzheimer’s disease. Cell Death Differ 10(6):698–708. doi:10.1038/sj.cdd.4401221

    Article  CAS  PubMed  Google Scholar 

  39. Ferreira ST, Klein WL (2011) The Abeta oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease. Neurobiol Learn Mem 96(4):529–543. doi:10.1016/j.nlm.2011.08.003

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Fonseca AC, Ferreiro E, Oliveira CR, Cardoso SM, Pereira CF (2013) Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim Biophys Acta 1832(12):2191–2203. doi:10.1016/j.bbadis.2013.08.007

    Article  CAS  PubMed  Google Scholar 

  42. 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 Alzheimer’s Dis JAD 20(2):625–636. doi:10.3233/JAD-2010-091369

    CAS  Google Scholar 

  43. Costa RO, Ferreiro E, Oliveira CR, Pereira CMF (2013) Inhibition of mitochondrial cytochrome c oxidase potentiates Aβ-induced ER stress and cell death in cortical neurons. Mol Cell Neurosci 52:1–8. doi:10.1016/j.mcn.2012.09.005

    Article  CAS  PubMed  Google Scholar 

  44. 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

    Article  CAS  PubMed  Google Scholar 

  45. 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

    Article  PubMed Central  PubMed  Google Scholar 

  46. Schapansky J, Olson K, Van Der Ploeg R, Glazner G (2007) NF-kappaB activated by ER calcium release inhibits Abeta-mediated expression of CHOP protein: enhancement by AD-linked mutant presenilin 1. Exp Neurol 208(2):169–176. doi:10.1016/j.expneurol.2007.04.009

    Article  CAS  PubMed  Google Scholar 

  47. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. 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

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Ho YS, Yang X, Lau JC, Hung CH, Wuwongse S, Zhang Q, Wang J, Baum L, So KF, Chang RC (2012) Endoplasmic reticulum stress induces tau pathology and forms a vicious cycle: implication in Alzheimer’s disease pathogenesis. J Alzheimer’s Dis JAD 28(4):839–854. doi:10.3233/JAD-2011-111037

    CAS  Google Scholar 

  50. Kins S, Crameri A, Evans DR, Hemmings BA, Nitsch RM, Gotz J (2001) Reduced protein phosphatase 2A activity induces hyperphosphorylation and altered compartmentalization of tau in transgenic mice. J Biol Chem 276(41):38193–38200. doi:10.1074/jbc.M102621200

    CAS  PubMed  Google Scholar 

  51. Nijholt DA, van Haastert ES, Rozemuller AJ, Scheper W, Hoozemans JJ (2012) The unfolded protein response is associated with early tau pathology in the hippocampus of tauopathies. J Pathol 226(5):693–702. doi:10.1002/path.3969

    Article  CAS  PubMed  Google Scholar 

  52. Abisambra JF, Jinwal UK, Blair LJ, O’Leary JC 3rd, Li Q, Brady S, Wang L, Guidi CE, Zhang B, Nordhues BA, Cockman M, Suntharalingham A, Li P, Jin Y, Atkins CA, Dickey CA (2013) Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J Neurosci Off J Soc Neurosci 33(22):9498–9507. doi:10.1523/JNEUROSCI.5397-12.2013

    Article  CAS  Google Scholar 

  53. Ferreiro E, Pereira CM (2012) Endoplasmic reticulum stress: a new playER in tauopathies. J Pathol 226(5):687–692. doi:10.1002/path.3977

    Article  CAS  PubMed  Google Scholar 

  54. Song J, Park KA, Lee WT, Lee JE (2014) Apoptosis signal regulating kinase 1 (ASK1): potential as a therapeutic target for Alzheimer’s disease. Int J Mol Sci 15(2):2119–2129. doi:10.3390/ijms15022119

    Article  PubMed Central  PubMed  Google Scholar 

  55. Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta (BBA) Mol Cell Res 1833(12):3460–3470. doi:10.1016/j.bbamcr.2013.06.028

    Article  CAS  Google Scholar 

  56. Akterin S, Cowburn RF, Miranda-Vizuete A, Jimenez A, Bogdanovic N, Winblad B, Cedazo-Minguez A (2006) Involvement of glutaredoxin-1 and thioredoxin-1 in beta-amyloid toxicity and Alzheimer’s disease. Cell Death Differ 13(9):1454–1465. doi:10.1038/sj.cdd.4401818

    Article  CAS  PubMed  Google Scholar 

  57. Gupta S, Giricz Z, Natoni A, Donnelly N, Deegan S, Szegezdi E, Samali A (2012) NOXA contributes to the sensitivity of PERK-deficient cells to ER stress. FEBS Lett 586(22):4023–4030. doi:10.1016/j.febslet.2012.10.002

    Article  CAS  PubMed  Google Scholar 

  58. 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

    Article  CAS  PubMed  Google Scholar 

  59. 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

    Article  CAS  PubMed  Google Scholar 

  60. Martinez JA, Zhang Z, Svetlov SI, Hayes RL, Wang KK, Larner SF (2010) Calpain and caspase processing of caspase-12 contribute to the ER stress-induced cell death pathway in differentiated PC12 cells. Apoptosis Int J Program Cell Death 15(12):1480–1493. doi:10.1007/s10495-010-0526-4

    Article  CAS  Google Scholar 

  61. Ferreiro E, Oliveira CR, Pereira CM (2008) The release of calcium from the endoplasmic reticulum induced by amyloid-beta and prion peptides activates the mitochondrial apoptotic pathway. Neurobiol Dis 30(3):331–342. doi:10.1016/j.nbd.2008.02.003

    Article  CAS  PubMed  Google Scholar 

  62. Vaux DL (2011) Apoptogenic factors released from mitochondria. Biochim Biophys Acta 1813(4):546–550. doi:10.1016/j.bbamcr.2010.08.002

    Article  CAS  PubMed  Google Scholar 

  63. Eisenberg-Lerner A, Bialik S, Simon HU, Kimchi A (2009) Life and death partners: apoptosis, autophagy and the cross-talk between them. Cell Death Differ 16(7):966–975. doi:10.1038/cdd.2009.33

    Article  CAS  PubMed  Google Scholar 

  64. Tooze SA, Schiavo G (2008) Liaisons dangereuses: autophagy, neuronal survival and neurodegeneration. Curr Opin Neurobiol 18(5):504–515. doi:10.1016/j.conb.2008.09.015

    Article  CAS  PubMed  Google Scholar 

  65. Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Naslund J, Mathews PM, Cataldo AM, Nixon RA (2005) Macroautophagy—a novel Beta-amyloid peptide-generating pathway activated in Alzheimer’s disease. J Cell Biol 171(1):87–98. doi:10.1083/jcb.200505082

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  66. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26(24):9220–9231. doi:10.1128/MCB.01453-06

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Jiang T, Yu JT, Zhu XC, Tan MS, Wang HF, Cao L, Zhang QQ, Shi JQ, Gao L, Qin H, Zhang YD, Tan L (2014) Temsirolimus promotes autophagic clearance of amyloid-beta and provides protective effects in cellular and animal models of Alzheimer’s disease. Pharmacol Res Off J Ital Pharmacol Soc. doi:10.1016/j.phrs.2014.02.008

    Google Scholar 

  68. Kim DS, Li B, Rhew KY, Oh HW, Lim HD, Lee W, Chae HJ, Kim HR (2012) The regulatory mechanism of 4-phenylbutyric acid against ER stress-induced autophagy in human gingival fibroblasts. Arch Pharm Res 35(7):1269–1278. doi:10.1007/s12272-012-0718-2

    Article  CAS  PubMed  Google Scholar 

  69. Paschen W, Mengesdorf T (2005) Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease–therapeutic potential. Pharmacol Ther 108(3):362–375. doi:10.1016/j.pharmthera.2005.05.008

    Article  CAS  PubMed  Google Scholar 

  70. Cawley K, Logue SE, Gorman AM, Zeng Q, Patterson J, Gupta S, Samali A (2013) Disruption of microRNA biogenesis confers resistance to ER stress-induced cell death upstream of the mitochondrion. PloS One 8(8):e73870. doi:10.1371/journal.pone.0073870

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  71. Yoshida H, Yoshizawa T, Shibasaki F, Shoji S, Kanazawa I (2002) Chemical chaperones reduce aggregate formation and cell death caused by the truncated Machado-Joseph disease gene product with an expanded polyglutamine stretch. Neurobiol Dis 10(2):88–99

    Article  CAS  PubMed  Google Scholar 

  72. Verhoef LG, Lindsten K, Masucci MG, Dantuma NP (2002) Aggregate formation inhibits proteasomal degradation of polyglutamine proteins. Hum Mol Genet 11(22):2689–2700

    Article  CAS  PubMed  Google Scholar 

  73. Winklhofer KF, Reintjes A, Hoener MC, Voellmy R, Tatzelt J (2001) Geldanamycin restores a defective heat shock response in vivo. J Biol Chem 276(48):45160–45167. doi:10.1074/jbc.M104873200

    Article  CAS  PubMed  Google Scholar 

  74. Piper PW (2001) The Hsp90 chaperone as a promising drug target. Curr Opin Investig Drugs 2(11):1606–1610

    CAS  PubMed  Google Scholar 

  75. Cuervo AM, Dice JF (2000) Age-related decline in chaperone-mediated autophagy. J Biol Chem 275(40):31505–31513. doi:10.1074/jbc.M002102200

    Article  CAS  PubMed  Google Scholar 

  76. Lund J, Tedesco P, Duke K, Wang J, Kim SK, Johnson TE (2002) Transcriptional profile of aging in C. elegans. Curr Biol CB 12(18):1566–1573

    Article  CAS  Google Scholar 

  77. Tonoki A, Kuranaga E, Tomioka T, Hamazaki J, Murata S, Tanaka K, Miura M (2009) Genetic evidence linking age-dependent attenuation of the 26S proteasome with the aging process. Mol Cell Biol 29(4):1095–1106. doi:10.1128/MCB.01227-08

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  78. Bali P, Pranpat M, Bradner J, Balasis M, Fiskus W, Guo F, Rocha K, Kumaraswamy S, Boyapalle S, Atadja P, Seto E, Bhalla K (2005) Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90: a novel basis for antileukemia activity of histone deacetylase inhibitors. J Biol Chem 280(29):26729–26734. doi:10.1074/jbc.C500186200

    Article  CAS  PubMed  Google Scholar 

  79. Ricobaraza A, Cuadrado-Tejedor M, Perez-Mediavilla A, Frechilla D, Del Rio J, Garcia-Osta A (2009) Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer’s disease mouse model. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol 34(7):1721–1732. doi:10.1038/npp.2008.229

    Article  CAS  Google Scholar 

  80. Boyce M, Bryant KF, Jousse C, Long K, Harding HP, Scheuner D, Kaufman RJ, Ma D, Coen DM, Ron D, Yuan J (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307(5711):935–939. doi:10.1126/science.1101902

    Article  CAS  PubMed  Google Scholar 

  81. Verfaillie T, Garg AD, Agostinis P (2013) Targeting ER stress induced apoptosis and inflammation in cancer. Cancer Lett 332(2):249–264. doi:10.1016/j.canlet.2010.07.016

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the grants from the National Natural Science Foundation of China to L.T. (81171209, 81371406) and J.T.Y. (81000544), the grants from the Shandong Provincial Natural Science Foundation to L.T. (ZR2011HZ001) and J.T.Y. (ZR2010HQ004), the Medicine and Health Science Technology Development Project of Shandong Province to L.T. (2011WSA02018) and J.T.Y. (2011WSA02020), and the Innovation Project for Postgraduates of Jiangsu Province to T.J. (CXLX13_561).

Conflicts of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China

    Jie-Qiong Li, Jin-Tai Yu & Lan Tan

  2. Department of Neurology, Qingdao Municipal Hospital, College of Medicine and Pharmaceutics, Ocean University of China, Qingdao, China

    Jin-Tai Yu & Lan Tan

  3. Department of Neurology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China

    Jin-Tai Yu, Teng Jiang & Lan Tan

Authors
  1. Jie-Qiong Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jin-Tai Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Teng Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lan Tan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jin-Tai Yu or Lan Tan.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, JQ., Yu, JT., Jiang, T. et al. Endoplasmic Reticulum Dysfunction in Alzheimer’s Disease. Mol Neurobiol 51, 383–395 (2015). https://doi.org/10.1007/s12035-014-8695-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8695-8

Keywords

Search

Navigation