Skip to main content

Advertisement

SpringerLink
Log in

Enhanced Amyloidogenic Processing of Amyloid Precursor Protein and Cell Death Under Prolonged Endoplasmic Reticulum Stress in Brain Endothelial Cells

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Cerebral amyloid angiopathy resulting from the deposition of misfolded amyloid beta (Aβ) peptide in the walls of brain’s blood vessels is exhibited by the majority of Alzheimer’s disease (AD) patients, suggesting that alterations in protein quality control contribute to AD-associated vascular dysfunction. The present work addressed the role of ER stress in the amyloidogenic amyloid precursor protein (APP) processing and subsequent Aβ generation in brain endothelial cells (ECs). For that purpose, the RBE4 cell line was exposed to the classical ER stressors thapsigargin or brefeldin A to mimic the altered ER homeostasis observed in AD. In treated cells, an increase in the levels of markers of ER stress (XBP1 and GRP78) and of the ER stress-induced apoptotic pathway (caspase-12, JNK, and CHOP) was observed concomitantly with the accumulation of reactive oxygen species. Under these conditions, a significant ER-to-mitochondria Ca2+ transfer was also found, which culminated in mitochondrial Ca2+ overload and activation of mitochondria-dependent apoptosis. Moreover, it was showed that prolonged ER stress induces intracellular APP accumulation, which colocalizes with the ER chaperone GRP78, and activation of β-secretase, leading to increased intracellular Aβ levels, together with a decrease in secreted Aβ. Finally, it was demonstrated that ER stress-induced changes in Aβ levels and apoptotic cell death can be ameliorated by a blocker of the mitochondrial Bax channel. These observations suggest that chronic ER stress triggers APP accumulation in early comportments along the secretory pathway in brain ECs and increases its amyloidogenic processing and Aβ generation leading to apoptotic cell death.

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
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

References

  1. Selkoe D, Mandelkow E, Holtzman D (2012) Deciphering Alzheimer disease. Cold Spring Harb Perspect Med 2(1):a011460

    Article  PubMed Central  PubMed  Google Scholar 

  2. Humpel C (2011) Chronic mild cerebrovascular dysfunction as a cause for Alzheimer’s disease? Exp Gerontol 46(4):225–232

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Sadowski M, Pankiewicz J, Scholtzova H, Li YS, Quartermain D, Duff K, Wisniewski T (2004) Links between the pathology of Alzheimer’s disease and vascular dementia. Neurochem Res 29(6):1257–1266

    Article  CAS  PubMed  Google Scholar 

  4. Kudo T, Imaizumi K, Tanimukai H, Katayama T, Sato N, Nakamura Y, Tanaka T, Kashiwagi Y, Jinno Y, Tohyama M, Takeda M (2000) Are cerebrovascular factors involved in Alzheimer’s disease? Neurobiol Aging 21(2):215–224

    Article  CAS  PubMed  Google Scholar 

  5. Sagare AP, Bell RD, Zlokovic BV (2012) Neurovascular dysfunction and faulty amyloid beta-peptide clearance in Alzheimer disease. Cold Spring Harb Perspect Med 2(10):a011452

  6. Attems J, Yamaguchi H, Saido TC, Thal DR (2010) Capillary CAA and perivascular Abeta-deposition: two distinct features of Alzheimer’s disease pathology. J Neurol Sci 299(1–2):155–162

    Article  CAS  PubMed  Google Scholar 

  7. 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

    Article  CAS  PubMed  Google Scholar 

  8. Gouras GK, Tsai J, Naslund J, Vincent B, Edgar M, Checler F, Greenfield JP, Haroutunian V, Buxbaum JD, Xu H, Greengard P, Relkin NR (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156(1):15–20

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Hayashi S, Sato N, Yamamoto A, Ikegame Y, Nakashima S, Ogihara T, Morishita R (2009) Alzheimer disease-associated peptide, amyloid beta40, inhibits vascular regeneration with induction of endothelial autophagy. Arterioscler Thromb Vasc Biol 29(11):1909–1915

    Article  CAS  PubMed  Google Scholar 

  10. Knobloch M, Konietzko U, Krebs DC, Nitsch RM (2007) Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging 28(9):1297–1306

    Article  CAS  PubMed  Google Scholar 

  11. Kouznetsova E, Klingner M, Sorger D, Sabri O, Grossmann U, Steinbach J, Scheunemann M, Schliebs R (2006) Developmental and amyloid plaque-related changes in cerebral cortical capillaries in transgenic Tg2576 Alzheimer mice. Int J Dev Neurosci 24(2–3):187–193

    Article  CAS  PubMed  Google Scholar 

  12. 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

    Article  CAS  PubMed  Google Scholar 

  13. Takahashi RH, Milner TA, Li F, Nam EE, Edgar MA, Yamaguchi H, Beal MF, Xu H, Greengard P, Gouras GK (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161(5):1869–1879

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Chisari M, Merlo S, Sortino MA, Salomone S (2010) Long-term incubation with beta-amyloid peptides impairs endothelium-dependent vasodilatation in isolated rat basilar artery. Pharmacol Res 61(2):157–161

    Article  CAS  PubMed  Google Scholar 

  15. Hsu MJ, Sheu JR, Lin CH, Shen MY, Hsu CY (2010) Mitochondrial mechanisms in amyloid beta peptide-induced cerebrovascular degeneration. Biochim Biophys Acta 1800(3):290–296

    Article  CAS  PubMed  Google Scholar 

  16. Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P (2012) Alzheimer culprits: cellular crossroads and interplay. Cell Signal 24(9):1831–1840

    Article  CAS  PubMed  Google Scholar 

  17. Hartmann T, Bieger SC, Bruhl B, Tienari PJ, Ida N, Allsop D, Roberts GW, Masters CL, Dotti CG, Unsicker K, Beyreuther K (1997) Distinct sites of intracellular production for Alzheimer’s disease A beta40/42 amyloid peptides. Nat Med 3(9):1016–1020

    Article  CAS  PubMed  Google Scholar 

  18. Lammich S, Kojro E, Postina R, Gilbert S, Pfeiffer R, Jasionowski M, Haass C, Fahrenholz F (1999) Constitutive and regulated alpha-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease. Proc Natl Acad Sci U S A 96(7):3922–3927

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Chyung AS, Greenberg BD, Cook DG, Doms RW, Lee VM (1997) Novel beta-secretase cleavage of beta-amyloid precursor protein in the endoplasmic reticulum/intermediate compartment of NT2N cells. J Cell Biol 138(3):671–680

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Chyung JH, Selkoe DJ (2003) Inhibition of receptor-mediated endocytosis demonstrates generation of amyloid beta-protein at the cell surface. J Biol Chem 278(51):51035–51043

    Article  CAS  PubMed  Google Scholar 

  21. LaFerla FM, Green KN, Oddo S (2007) Intracellular amyloid-beta in Alzheimer’s disease. Nat Rev Neurosci 8(7):499–509

    Article  CAS  PubMed  Google Scholar 

  22. Perez RG, Soriano S, Hayes JD, Ostaszewski B, Xia W, Selkoe DJ, Chen X, Stokin GB, Koo EH (1999) Mutagenesis identifies new signals for beta-amyloid precursor protein endocytosis, turnover, and the generation of secreted fragments, including Abeta42. J Biol Chem 274(27):18851–18856

    Article  CAS  PubMed  Google Scholar 

  23. Shin RW, Saido TC, Maeda M, Kitamoto T (2005) Novel alpha-secretase cleavage of Alzheimer’s amyloid beta precursor protein in the endoplasmic reticulum of COS7 cells. Neurosci Lett 376(1):14–19

    Article  CAS  PubMed  Google Scholar 

  24. Yamamoto K, Fujii R, Toyofuku Y, Saito T, Koseki H, Hsu VW, Aoe T (2001) The KDEL receptor mediates a retrieval mechanism that contributes to quality control at the endoplasmic reticulum. EMBO J 20(12):3082–3091

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Pereira CMF (2013) Crosstalk between endoplasmic reticulum stress and protein misfolding in neurodegenerative diseases. ISRN Cell Biology 2012:1–22

    Article  Google Scholar 

  26. Grimm S (2012) The ER-mitochondria interface: the social network of cell death. Biochim Biophys Acta 1823(2):327–334

    Article  CAS  PubMed  Google Scholar 

  27. Chadwick W, Mitchell N, Martin B, Maudsley S (2012) Therapeutic targeting of the endoplasmic reticulum in Alzheimer’s disease. Curr Alzheimer Res 9(1):110–119

    Article  CAS  PubMed  Google Scholar 

  28. 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

    Article  CAS  PubMed  Google Scholar 

  29. Kogel D, Schomburg R, Schurmann T, Reimertz C, Konig HG, Poppe M, Eckert A, Muller WE, Prehn JH (2003) The amyloid precursor protein protects PC12 cells against endoplasmic reticulum stress-induced apoptosis. J Neurochem 87(1):248–256

  30. Roux F, Durieu-Trautmann O, Chaverot N, Claire M, Mailly P, Bourre JM, Strosberg AD, Couraud PO (1994) Regulation of gamma-glutamyl transpeptidase and alkaline phosphatase activities in immortalized rat brain microvessel endothelial cells. J Cell Physiol 159(1):101–113

    Article  CAS  PubMed  Google Scholar 

  31. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  CAS  PubMed  Google Scholar 

  32. Cathcart R, Schwiers E, Ames BN (1983) Detection of picomole levels of hydroperoxides using a fluorescent dichlorofluorescein assay. Anal Biochem 134(1):111–116

    Article  CAS  PubMed  Google Scholar 

  33. Choy RW, Cheng Z, Schekman R (2012) Amyloid precursor protein (APP) traffics from the cell surface via endosomes for amyloid beta (Abeta) production in the trans-Golgi network. Proc Natl Acad Sci U S A 109(30):E2077–E2082

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Cregan SP, MacLaurin JG, Craig CG, Robertson GS, Nicholson DW, Park DS, Slack RS (1999) Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J Neurosci 19(18):7860–7869

    CAS  PubMed  Google Scholar 

  35. Bolte S, Cordelieres FP (2006) A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 224(Pt 3):213–232

    Article  CAS  PubMed  Google Scholar 

  36. 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 Alzheimers Dis 28(4):839–854

    CAS  PubMed  Google Scholar 

  37. Nutt LK, Chandra J, Pataer A, Fang B, Roth JA, Swisher SG, O’Neil RG, McConkey DJ (2002) Bax-mediated Ca2+ mobilization promotes cytochrome c release during apoptosis. J Biol Chem 277(23):20301–20308

    Article  CAS  PubMed  Google Scholar 

  38. Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C (2008) Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 27(3):285–299

    Article  CAS  PubMed  Google Scholar 

  39. Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18(24):3066–3077

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Kaufman RJ, Malhotra JD (2014) Calcium trafficking integrates endoplasmic reticulum function with mitochondrial bioenergetics. Biochim Biophys Acta 1843:2233–2239

  41. Ferreiro E, Costa R, Marques S, Cardoso SM, Oliveira CR, Pereira CM (2008) Involvement of mitochondria in endoplasmic reticulum stress-induced apoptotic cell death pathway triggered by the prion peptide PrP(106–126). J Neurochem 104(3):766–776

    CAS  PubMed  Google Scholar 

  42. Fonseca AC, Moreira PI, Oliveira CR, Cardoso SM, Pinton P, Pereira CF (2014) Amyloid-beta disrupts calcium and redox homeostasis in brain endothelial cells. Mol Neurobiol. Epub ahead of print

  43. Pereira C, Santos MS, Oliveira C (1998) Mitochondrial function impairment induced by amyloid beta-peptide on PC12 cells. Neuroreport 9(8):1749–1755

    Article  CAS  PubMed  Google Scholar 

  44. Dickhout JG, Hossain GS, Pozza LM, Zhou J, Lhotak S, Austin RC (2005) Peroxynitrite causes endoplasmic reticulum stress and apoptosis in human vascular endothelium: implications in atherogenesis. Arterioscler Thromb Vasc Biol 25(12):2623–2629

    Article  CAS  PubMed  Google Scholar 

  45. Tang X, Luo YX, Chen HZ, Liu DP (2014) Mitochondria, endothelial cell function, and vascular diseases. Front Physiol 5:175

    Article  PubMed Central  PubMed  Google Scholar 

  46. Basha B, Samuel SM, Triggle CR, Ding H (2012) Endothelial dysfunction in diabetes mellitus: possible involvement of endoplasmic reticulum stress? Exp Diabetes Res 2012:481840

    Article  PubMed Central  PubMed  Google Scholar 

  47. 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

    CAS  PubMed  Google Scholar 

  48. 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

    Article  CAS  PubMed  Google Scholar 

  49. Sano R, Reed JC (2013) ER stress-induced cell death mechanisms. Biochim Biophys Acta 1833(12):3460–3470

    Article  CAS  PubMed  Google Scholar 

  50. Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E, Mori M (2001) Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway. Proc Natl Acad Sci U S A 98(19):10845–10850

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Han J, Back SH, Hur J, Lin YH, Gildersleeve R, Shan J, Yuan CL, Krokowski D, Wang S, Hatzoglou M, Kilberg MS, Sartor MA, Kaufman RJ (2013) ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat Cell Biol 15(5):481–490

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Gross E, Sevier CS, Heldman N, Vitu E, Bentzur M, Kaiser CA, Thorpe C, Fass D (2006) Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p. Proc Natl Acad Sci U S A 103(2):299–304

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Szado T, Vanderheyden V, Parys JB, De Smedt H, Rietdorf K, Kotelevets L, Chastre E, Khan F, Landegren U, Soderberg O, Bootman MD, Roderick HL (2008) Phosphorylation of inositol 1,4,5-trisphosphate receptors by protein kinase B/Akt inhibits Ca2+ release and apoptosis. Proc Natl Acad Sci U S A 105(7):2427–2432

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Ferreiro E, Oliveira CR, Pereira C (2004) Involvement of endoplasmic reticulum Ca2+ release through ryanodine and inositol 1,4,5-triphosphate receptors in the neurotoxic effects induced by the amyloid-beta peptide. J Neurosci Res 76(6):872–880

    Article  CAS  PubMed  Google Scholar 

  56. Morais Cardoso S, Swerdlow RH, Oliveira CR (2002) Induction of cytochrome c-mediated apoptosis by amyloid beta 25–35 requires functional mitochondria. Brain Res 931(2):117–125

    Article  CAS  PubMed  Google Scholar 

  57. Resende R, Ferreiro E, Pereira C, Resende de Oliveira C (2008) Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1–42: involvement of endoplasmic reticulum calcium release in oligomer-induced cell death. Neuroscience 155(3):725–737

    Article  CAS  PubMed  Google Scholar 

  58. Brookes PS, Yoon Y, Robotham JL, Anders MW, Sheu SS (2004) Calcium, ATP, and ROS: a mitochondrial love–hate triangle. Am J Physiol Cell Physiol 287(4):C817–C833

    Article  CAS  PubMed  Google Scholar 

  59. Hitomi J, Katayama T, Taniguchi M, Honda A, Imaizumi K, Tohyama M (2004) Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neurosci Lett 357(2):127–130

    Article  CAS  PubMed  Google Scholar 

  60. Chen GJ, Xu J, Lahousse SA, Caggiano NL, de la Monte SM (2003) Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. J Alzheimers Dis 5(3):209–228

    PubMed  Google Scholar 

  61. Kitazume S, Tachida Y, Kato M, Yamaguchi Y, Honda T, Hashimoto Y, Wada Y, Saito T, Iwata N, Saido T, Taniguchi N (2010) Brain endothelial cells produce amyloid {beta} from amyloid precursor protein 770 and preferentially secrete the O-glycosylated form. J Biol Chem 285(51):40097–40103

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Xu J, Chen S, Ku G, Ahmed SH, Chen H, Hsu CY (2001) Amyloid beta peptide-induced cerebral endothelial cell death involves mitochondrial dysfunction and caspase activation. J Cereb Blood Flow Metab 21(6):702–710

    Article  CAS  PubMed  Google Scholar 

  63. Bulbarelli A, Lonati E, Brambilla A, Orlando A, Cazzaniga E, Piazza F, Ferrarese C, Masserini M, Sancini G (2012) Abeta42 production in brain capillary endothelial cells after oxygen and glucose deprivation. Mol Cell Neurosci 49(4):415–422

    Article  CAS  PubMed  Google Scholar 

  64. Pereira ER, Frudd K, Awad W, Hendershot LM (2014) Endoplasmic reticulum (ER) stress and hypoxia response pathways interact to potentiate hypoxia-inducible factor 1 (HIF-1) transcriptional activity on targets like vascular endothelial growth factor (VEGF). J Biol Chem 289(6):3352–3364

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Chami L, Checler F (2012) BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and beta-amyloid production in Alzheimer’s disease. Mol Neurodegener 7:52

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Liu B, Zhu Y, Zhou J, Wei Y, Long C, Chen M, Ling Y, Ge J, Zhuo Y (2014) Endoplasmic reticulum stress promotes amyloid-beta peptides production in RGC-5 cells. Cell Stress Chaperones

  67. Cupers P, Bentahir M, Craessaerts K, Orlans I, Vanderstichele H, Saftig P, De Strooper B, Annaert W (2001) The discrepancy between presenilin subcellular localization and gamma-secretase processing of amyloid precursor protein. J Cell Biol 154(4):731–740

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Vetrivel KS, Thinakaran G (2006) Amyloidogenic processing of beta-amyloid precursor protein in intracellular compartments. Neurology 66(2 Suppl 1):S69–S73

    Article  CAS  PubMed  Google Scholar 

  69. Domingues SC, Henriques AG, Wu W, Da Cruz e Silva EF, Da Cruz e Silva OA (2007) Altered subcellular distribution of the Alzheimer’s amyloid precursor protein under stress conditions. Ann N Y Acad Sci 1096:184–195

    Article  CAS  PubMed  Google Scholar 

  70. Park HJ, Shabashvili D, Nekorchuk MD, Shyqyriu E, Jung JI, Ladd TB, Moore BD, Felsenstein KM, Golde TE, Kim SH (2012) Retention in endoplasmic reticulum 1 (RER1) modulates amyloid-beta (Abeta) production by altering trafficking of gamma-secretase and amyloid precursor protein (APP). J Biol Chem 287(48):40629–40640

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. 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

    Article  CAS  PubMed  Google Scholar 

  72. Urano Y, Ochiai S, Noguchi N (2013) Suppression of amyloid-beta production by 24S-hydroxycholesterol via inhibition of intracellular amyloid precursor protein trafficking. FASEB J 27(10):4305–4315

    Article  CAS  PubMed  Google Scholar 

  73. 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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  74. Folin M, Baiguera S, Tommasini M, Guidolin D, Conconi MT, De Carlo E, Nussdorfer GG, Parnigotto PP (2005) Effects of beta-amyloid on rat neuromicrovascular endothelial cells cultured in vitro. Int J Mol Med 15(6):929–935

    CAS  PubMed  Google Scholar 

  75. Cantara S, Ziche M, Donnini S (2005) Opposite effects of beta amyloid on endothelial cell survival: role of fibroblast growth factor-2 (FGF-2). Pharmacol Rep 57(Suppl):138–143

    PubMed  Google Scholar 

  76. Balcells M, Wallins JS, Edelman ER (2008) Amyloid beta toxicity dependent upon endothelial cell state. Neurosci Lett 441(3):319–322

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Ana I. Plácido has a PhD fellowship from the Portuguese research council Fundação para a Ciência e Tecnologia (SFRH/BD/73388/2010).

The work was supported by PEst-C/SAU/LA0001/2013–2014, Gabinete de Apoio à Investigação (GAI)–Faculty of Medicine, University of Coimbra (project MOREIRA05.01.13) and Banco Santader Totta.

The uthors are grateful to the Microscopy Imaging Center of Coimbra, at the Center for Neuroscience and Cell Biology (MICC-CNC).

Conflict of Interest

The author declares no conflicts of interest that are directly relevant to the content of this article.

Author information

Authors and Affiliations

  1. Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga; Faculty of Medicine, Pólo I, 3004-504, Coimbra, Portugal

    Ana I. Plácido, Catarina R. Oliveira, Paula I. Moreira & Cláudia Maria F. Pereira

Authors
  1. Ana I. Plácido
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catarina R. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paula I. Moreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cláudia Maria F. Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Cláudia Maria F. Pereira.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Plácido, A.I., Oliveira, C.R., Moreira, P.I. et al. Enhanced Amyloidogenic Processing of Amyloid Precursor Protein and Cell Death Under Prolonged Endoplasmic Reticulum Stress in Brain Endothelial Cells. Mol Neurobiol 51, 571–590 (2015). https://doi.org/10.1007/s12035-014-8819-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-014-8819-1

Keywords

Search

Navigation