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Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells.
Biochim Biophys Acta 2013; 1832(12):2191-203BB

Abstract

Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration.

Authors+Show Affiliations

Center for Neuroscience and Cell Biology, University of Coimbra, Largo Marquês de Pombal, 3004-517 Coimbra, Portugal; Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Apartado 3046, 3001-401 Coimbra, Portugal.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23994613

Citation

Fonseca, Ana Catarina R G., et al. "Activation of the Endoplasmic Reticulum Stress Response By the Amyloid-beta 1-40 Peptide in Brain Endothelial Cells." Biochimica Et Biophysica Acta, vol. 1832, no. 12, 2013, pp. 2191-203.
Fonseca AC, Ferreiro E, Oliveira CR, et al. Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochim Biophys Acta. 2013;1832(12):2191-203.
Fonseca, A. C., Ferreiro, E., Oliveira, C. R., Cardoso, S. M., & Pereira, C. F. (2013). Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. Biochimica Et Biophysica Acta, 1832(12), pp. 2191-203. doi:10.1016/j.bbadis.2013.08.007.
Fonseca AC, et al. Activation of the Endoplasmic Reticulum Stress Response By the Amyloid-beta 1-40 Peptide in Brain Endothelial Cells. Biochim Biophys Acta. 2013;1832(12):2191-203. PubMed PMID: 23994613.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells. AU - Fonseca,Ana Catarina R G, AU - Ferreiro,Elisabete, AU - Oliveira,Catarina R, AU - Cardoso,Sandra M, AU - Pereira,Cláudia F, Y1 - 2013/08/28/ PY - 2013/02/26/received PY - 2013/07/28/revised PY - 2013/08/20/accepted PY - 2013/9/3/entrez PY - 2013/9/3/pubmed PY - 2014/2/22/medline KW - 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide KW - AD KW - AIF KW - AM KW - APP KW - ATF KW - Alzheimer's disease KW - Amyloid-beta peptide KW - Apoptosis KW - Aβ KW - BBB KW - CAAT/enhancer binding protein homologous protein KW - CHOP KW - Calcium homeostasis KW - DMSO KW - ECF KW - ECs KW - ER KW - Endoplasmic reticulum stress KW - Endothelial cells KW - GAPDH KW - GRP78 KW - IRE1 KW - JNK KW - LDH KW - LRP KW - MTT KW - NAD+ KW - NADH KW - PARP1 KW - PERK KW - PI KW - PS KW - PVDF KW - RAGE KW - RBE4 KW - RT KW - Ry KW - RyR KW - SDS-PAGE KW - SDS-polyacrylamide gel KW - SERCA KW - TATA-binding protein KW - TBP KW - TBS-T KW - TBS-Tween KW - TUNEL KW - ThS KW - UPR KW - WB KW - Western blot KW - X-box binding protein-1 KW - XBP-1 KW - acetoxymethyl ester KW - activating transcription factor KW - amyloid precursor protein KW - amyloid-beta KW - apoptosis-inducing factor KW - bFGF KW - basic fibroblast growth factor KW - blood–brain barrier KW - c-jun N-terminal kinase KW - dimethyl sulfoxide KW - eIF2α KW - endoplasmic reticulum KW - endothelial cells KW - enhanced chemifluorescence KW - glucose-regulated protein of 78kDa KW - glyceraldehyde-3-phosphate dehydrogenase KW - inositol-requiring protein-1 KW - lactate dehydrogenase KW - low-density lipoprotein receptor-related protein KW - mitochondrial membrane potential KW - nicotinamide adenine dinucleotide KW - oxidized nicotinamide adenine dinucleotide KW - poly(ADP-ribose) polymerase 1 KW - polyvinylidene difluoride KW - presenilinM KW - propidium iodide KW - protein kinase RNA-like ER kinase KW - rat brain endothelial cell line KW - receptor for advanced glycation end products KW - room temperature KW - ryanodine KW - ryanodine receptor KW - sarco/ER Ca(2+) ATPase KW - terminal deoxynucleotidyl transferase dUTP nick-end labeling KW - thioflavine S KW - unfolded protein response KW - Δψmit KW - α subunit of eukaryotic translation initiation factor 2 SP - 2191 EP - 203 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1832 IS - 12 N2 - Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. Finally, Aβ1-40 was shown to activate both mitochondria-dependent and -independent apoptotic cell death pathways. Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/23994613/Activation_of_the_endoplasmic_reticulum_stress_response_by_the_amyloid_beta_1_40_peptide_in_brain_endothelial_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0925-4439(13)00272-X DB - PRIME DP - Unbound Medicine ER -