The role of proteotoxic stress in vascular
dysfunction in the pathogenesis of Alzheimer’s
disease

• Authors: Ana Catarina R.G. Fonseca , Rosa Resende , Sandra M. Cardoso , Cláudia F. Pereira
• Languages of publication: EN

Abstracts

EN

Alzheimer’s disease (AD) is the principal cause of
dementia in the elderly; however, its prevalence is increasing
due to the fact that current pharmaceuticals used to manage
the symptoms are not capable of preventing, halting, or
reversing disease progression. In the last decade, evidence
has accumulated to support the hypothesis that a primary
cerebral vascular dysfunction initiates the cascade of
events that leads to neuronal injury and the subsequent
cognitive decline observed in AD. The mechanisms
underlying these vascular defects and their relationship
with neurodegeneration are still poorly understood
however. It is pathologically known that cerebrovascular
dysfunctions can induce the deposition of amyloid-β (Aβ),
an amyloidogenic and toxic peptide that in turn causes
cerebrovascular degeneration. Mammalian cells regulate
proteostasis and the functioning of intracellular organelles
through diverse mechanisms such as the Unfolded Protein
Response, the Ubiquitin-Proteasome System and autophagy;
however, when these mechanisms cannot compensate
for perturbations in homeostasis, the cell undergoes
programmed death via apoptosis. This review summarizes
recent studies that together correlate the deregulation
of protein quality control pathways with dysfunction of
vascular endothelial cells of the brain in AD, thus supporting
the hypothesis that it is the vicious, progressive failure of
the proteostatic network and endothelial activation that
underlies the cerebrovascular changes that symptomize AD.

Keywords

EN

Alzheimer‘s disease; Aβ peptide; endothelialcells; endoplasmic reticulum; Unfolded Protein Response,; calcium homeostasis; redox homeostasis; Ubiquitinproteasomesystem, autophagy, apoptosis

• Publisher: De Gruyter Open
• Journal: Endoplasmic Reticulum Stress in Diseases
• Year: 2015
• Volume: 2
• Issue: 1

Dates

accepted

13 - 5 - 2014

online

20 - 8 - 2015

received

26 - 11 - 2014

Contributors

author

Ana Catarina R.G. Fonseca

• CNC
  – Center for Neuroscience and Cell Biology, University of Coimbra,
  Coimbra, Portugal

author

Rosa Resende

• CNC
  – Center for Neuroscience and Cell Biology, University of Coimbra,
  Coimbra, Portugal

author

Sandra M. Cardoso

• CNC
  – Center for Neuroscience and Cell Biology, University of Coimbra,
  Coimbra, Portugal
• Faculty of
  Medicine, University of Coimbra, Coimbra, Portugal

author

Cláudia F. Pereira

• Center for
  Neuroscience and Cell Biology, University of Coimbra, 3004-517
  Coimbra, Portugal
• Faculty of
  Medicine, University of Coimbra, Coimbra, Portugal

References

• [1] Thies W., Bleiler L., Alzheimer’s disease facts and figures,Alzheimers Dement., 2013, 9, 208-245.
• [2] Ferri C.P., Prince M., Brayne C., Brodaty H., Fratiglioni L.,Ganguli M., et al., Global prevalence of dementia: a Delphiconsensus study, Lancet, 2005, 366, 2112-2117.
• [3] Reitz C., Brayne C., Mayeux R., Epidemiology of Alzheimerdisease, Nat. Rev. Neurol., 2011, 7, 137-152.[Crossref]
• [4] Casserly I., Topol E., Convergence of atherosclerosis andAlzheimer’s disease: inflammation, cholesterol, andmisfolded proteins, Lancet, 2004, 363, 1139-1146.
• [5] Petersen R.C., Doody R., Kurz A., Mohs R.C., Morris J.C.,Rabins P.V., et al., Current concepts in mild cognitiveimpairment, Arch. Neurol., 2001, 58, 1985-1992.[Crossref]
• [6] Langbaum J.B., Fleisher A.S., Chen K., Ayutyanont N., LoperaF., Quiroz Y.T., et al., Ushering in the study and treatmentof preclinical Alzheimer disease, Nat. Rev. Neurol., 2013, 9,371-381.[Crossref]
• [7] Blennow K., de Leon M.J. and Zetterberg H., Alzheimer’sdisease, Lancet, 2006, 368, 387-403.
• [8] Cruts M., Theuns J., Van Broeckhoven C., Locus-specificmutation databases for neurodegenerative brain diseases,Hum. Mutat., 2012, 33, 1340-1344.[Crossref]
• [9] Karch C.M., Goate A.M., Alzheimer’s disease risk genes andmechanisms of disease pathogenesis. Biol. Psychiatry, 2015,77, 43-51.[Crossref]
• [10] Qiu C., Preventing Alzheimer’s disease by targeting vascularrisk factors: hope and gap, J. Alzheimers Dis., 2012, 32,721-731.
• [11] De Sole P., Rossi C., Chiarpotto M., Ciasca G., Bocca B.,Alimonti A., et al., Possible relationship between Al/ferritincomplex and Alzheimer’s disease, Clin. Biochem., 2013, 46,89-93.[Crossref]
• [12] Chow V.W., Mattson M.P., Wong P.C., Gleichmann M., Anoverview of APP processing enzymes and products, NeuromolecularMed., 2011, 12, 1-12.[Crossref]
• [13] Nalivaeva N.N., Turner A.J., The amyloid precursor protein:a biochemical enigma in brain development, function anddisease, FEBS Lett., 2013, 587, 2046-2054.
• [14] Kim W., Hecht M.H., Sequence determinants of enhancedamyloidogenicity of Alzheimer A{beta}42 peptide relative toA{beta}40, J. Biol. Chem., 2005, 280, 35069-35076.
• [15] LaFerla F.M., Green K.N., Oddo S., Intracellular amyloid-betain Alzheimer’s disease, Nat. Rev. Neurosci., 2007, 8, 499-509.[Crossref]
• [16] Karran E., Mercken M., De Strooper B., The amyloid cascadehypothesis for Alzheimer’s disease: an appraisal for thedevelopment of therapeutics, Nat .Rev. Drug Discov., 2011, 10,698-712.[Crossref]
• [17] De-Paula V.J., Radanovic M., Diniz B.S., Forlenza O.V.,Alzheimer’s disease, Subcell. Biochem., 2012, 65 329-352.
• [18] Resende R., Ferreiro E., Pereira C., Oliveira C.R., Neurotoxiceffect of oligomeric and fibrillar species of Aβ1-42 peptide:involvement of endoplasmic reticulum calcium release inoligomers-induced cell death, Neuroscience, 2008a, 155,725-737.
• [19] He Y., Zheng M.M., Ma Y., Han X.J., Ma X.Q., Qu C.Q., etal., Soluble oligomers and fibrillar species of amyloidbeta-peptide differentially affect cognitive functions andhippocampal inflammatory response, Biochem. Biophys. Res.Commun., 2012, 429, 125-130.
• [20] Selkoe D.J., Alzheimer’s disease: genes, proteins and therapy,Physiol. Rev., 2001, 81, 741-766.
• [21] Jonsson T., Atwal J.K., Steinberg S., Snaedal J., JonssonP.V., Bjornsson S., et al., A mutation in APP protects againstAlzheimer’s disease and age-related cognitive decline,Nature, 2012, 488, 96-99.
• [22] Wilcock D.M., Griffin W.S., Down’s syndrome, neuroinflammation,and Alzheimer neuropathogenesis, J.Neuroinflammation, 2013, 10, 84.
• [23] Zigman W.B., Atypical aging in down syndrome, Dev. Disabil.Res. Rev., 2013, 18, 51-67.[Crossref]
• [24] Oddo S., Caccamo A., Shepherd J.D., Murphy M.P., GoldeT.E., Kayed R., et al., Triple-transgenic model of Alzheimer’sdisease with plaques and tangles: intracellular Abeta andsynaptic dysfunction, Neuron, 2003, 39, 409-421.[Crossref]
• [25] Lalonde R., Fukuchi K., Strazielle C., Neurologic and motordysfunctions in APP transgenic mice, Rev. Neurosci., 2012, 23,363-379.
• [26] Saito T., Matsuba Y., Mihira N., Takano J., Nilsson P., ItoharaS., Iwata N., Saido T.C., Single App knock-in mouse models ofAlzheimer’s disease, Nat. Neurosci., 2014, 17, 661-366.[Crossref]
• [27] Lewis T.L., Cao D., Lu H., Mans R.A., Su Y.R., Jungbauer L., etal., Overexpression of human apolipoprotein A-I preservescognitive function and attenuates neuroinflammation andcerebral amyloid angiopathy in a mouse model of Alzheimerdisease, J. Biol. Chem., 2010, 285, 36958-36968.
• [28] Kitazawa M., Medeiros R., Laferla F.M., Transgenic mousemodels of Alzheimer disease: developing a better model asa tool for therapeutic interventions, Curr. Pharm. Des., 2012,18, 1131-1147.[Crossref]
• [29] Resende R., Ferreiro E., Pereira C., Oliveira C.R., ER stress isinvolved in Aβ-induced GSK-3β activation and tau phosphorylation,J. Neurosci. Res., 2008b, 86 (9), 2091-2099.[Crossref]
• [30] Fonseca A.C.R.G., Proença T., Resende R., Oliveira C.R.,Pereira C.M.F., Neuroprotective effects of statins in an in vitromodel of Alzheimer’s disease, J. Alzheimers Dis., 2009, 17,503-517.[Crossref]
• [31] Fonseca A.C.R.G., Resende R., Oliveira C.R., Pereira C.M.F.,Cholesterol and statins in Alzheimer’s disease: currentcontroversies, Exp. Neurol., 2010, 223, 282-293.
• [32] Agostinho P., Cunha R.A., Oliveira C., Neuroinflammation,oxidative stress and the pathogenesis of Alzheimer’s disease,Curr. Pharm. Des., 2010, 16, 2766-2778.[Crossref]
• [33] Costa R.O., Ferreiro E., Martins I., Santana I., CardosoS.M., Oliveira C.R., et al., Amyloid beta-induced ER stressis enhanced under mitochondrial dysfunction conditions,Neurobiol. Aging, 2012, 33, 824 e5-16.[Crossref]
• [34] Sheng M., Sabatini B.L., Sudhof T.C., Synapses andAlzheimer’s disease, Cold Spring Harb. Perspect. Biol., 2012,4, a005777.
• [35] Ferreira I.L., Ferreiro E., Schmidt J., Cardoso J.M., PereiraC.M., Carvalho A.L., Oliveira C.R., Rego A.C. Aβ and NMDARactivation cause mitochondrial dysfunction involving ERcalcium release Neurobiol. Aging, 2015, 36, 680-692.
• [36] Zlokovic B.V., Neurovascular pathways to neurodegenerationin Alzheimer’s disease and other disorders, Nat. Rev.Neurosci., 2011, 12, 723-738.
• [37] Jia W., Martin T.A., Zhang G., Jiang W.G., Junctional adhesionmolecules in cerebral endothelial tight junction and brainmetastasis, Anticancer Res., 2013, 33, 2353-2359.
• [38] Attems J., Jellinger K., Thal D.R.. Van Nostrand W., Review:sporadic cerebral amyloid angiopathy, Neuropathol. Appl.Neurobiol., 2011, 37, 75-93.[Crossref]
• [39] Sanchez A., Tripathy D., Luo J., Yin X., Martinez J., GrammasP., Neurovascular unit and the effects of dosage in VEGFtoxicity: role for oxidative stress and thrombin, J. AlzheimersDis., 2013, 34, 281-291.
• [40] Bertini G., Bramanti P., Constantin G., Pellitteri M., RaduB.M., Radu M., et al., New players in the neurovascular unit:Insights from experimental and clinical epilepsy, Neurochem.Int., 2013, 63, 652-659.[Crossref]
• [41] Grammas P., Neurovascular dysfunction, inflammation andendothelial activation: implications for the pathogenesis ofAlzheimer’s disease, J. Neuroinflammation, 2011, 8, 26.[Crossref]
• [42] von Tell D., Armulik A., Betsholtz C., Pericytes and vascularstability, Exp. Cell Res., 2006, 312, 623-629.
• [43] Lai C.H., Kuo K.H., The critical component to establish in vitroBBB model: Pericyte, Brain Res. Brain Res. Rev., 2005, 50,258-265.[Crossref]
• [44] Krueger M., Bechmann I., CNS pericytes: concepts, misconceptions,and a way out, Glia, 2010, 58, 1-10.[Crossref]
• [45] Hawkins B.T., Davis T.P., The blood-brain barrier/neurovascular unit in health and disease, Pharmacol. Rev.,2005, 57, 173-185.[Crossref]
• [46] Iadecola C., Neurovascular regulation in the normal brain andin Alzheimer’s disease, Nat. Rev. Neurosci., 2004, 5, 347-360.[Crossref]
• [47] Leung K.K., Bartlett J.W., Barnes J., Manning E.N., Ourselin S.,Fox N.C., Cerebral atrophy in mild cognitive impairment andAlzheimer disease: rates and acceleration, Neurology, 2013,80, 648-654.[Crossref]
• [48] Formichi P., Parnetti L., Radi E., Cevenini G., Dotti M.T. andFederico A., CSF Biomarkers Profile in CADASIL-A Model ofPure Vascular Dementia: Usefulness in Differential Diagnosisin the Dementia Disorder, Int. J. Alzheimers Dis., 2010, pii:959257.
• [49] Beach T.G., Wilson J.R., Sue L.I., Newell A., Poston M.,Cisneros R., et al., Circle of Willis atherosclerosis: associationwith Alzheimer’s disease, neuritic plaques and neurofibrillarytangles, Acta Neuropathol., 2007, 113, 13-21.
• [50] Dickstein D., Walsh J., Brautigam H., Stockton S.J., Gandy S.,Hof P., Role of vascular risk factors and vascular dysfunctionin Alzheimer’s disease, Mt. Sinai J. Med., 2010, 77, 82-102.[Crossref]
• [51] Knopman D., Roberts R., Vascular risk factors: imaging andneuropathologic correlates, J. Alzheimers Dis., 2010, 20,699-709.[Crossref]
• [52] Oulhaj A., Refsum H., Beaumont H., Williams J., King E.,Jacoby R., et al., Homocysteine as a predictor of cognitivedecline in Alzheimer’s disease, Int. J. Geriatr. Psychiatry,2010, 25, 82-90.
• [53] Klohs J., Rudin M., Shimshek D.R., Beckmann N., Imaging ofcerebrovascular pathology in animal models of Alzheimer’sdisease, Front. Aging Neurosci., 2014, 6, 32.
• [54] Xu W., Xu F., Anderson M.E., Kotarba A.E., Davis J., RobinsonJ.K., et al., Cerebral microvascular rather than parenchymalamyloid-beta protein pathology promotes early cognitiveimpairment in transgenic mice, J. Alzheimers Dis., 2014, 38,621-632.
• [55] Gibson G.E., Shi Q., A mitocentric view of Alzheimer’s diseasesuggests multi-faceted treatments, J. Alzheimers Dis., 2010,20, S591-S607.[Crossref]
• [56] Winkler E.A., Nishida Y., Sagare A.P., Rege S.V., Bell R.D.,Perlmutter D., et al., GLUT1 reductions exacerbate Alzheimer’sdisease vasculo-neuronal dysfunction and degeneration, Nat.Neurosci., 2015, 18, 521-530.[Crossref]
• [57] Ujiie M., Dickstein D.L., Carlow D.A., Jefferies W.A.Blood-brain barrier permeability precedes senile plaqueformation in an Alzheimer disease model, Microcirculation,2003, 10, 463-470.
• [58] Dickstein D.L., Biron K.E., Ujiie M., Pfeifer C.G., Jeffries A.R.and Jefferies WA, Abeta peptide immunization restoresblood-brain barrier integrity in Alzheimer disease, FASEB J.,2006, 20(3), 426-433.[Crossref]
• [59] Carrano A., Hoozemans J.J., van der Vies S.M., RozemullerA.J., van Horssen J., de Vries H.E., Amyloid Beta inducesoxidative stress-mediated blood-brain barrier changes incapillary amyloid angiopathy, Antioxid. Redox Signal., 2011,15, 1167-1178.[Crossref]
• [60] Sharma H.S., Castellani R.J., Smith M.A., Sharma A., Theblood-brain barrier in Alzheimer’s disease: novel therapeutictargets and nanodrug delivery, Int. Rev. Neurobiol., 2012, 102,47-90.[Crossref]
• [61] Kook S.Y., Hong H.S., Moon M., Ha C.M., Chang S., Mook-JungI., Abeta(1)(-)(4)(2)-RAGE interaction disrupts tight junctionsof the blood-brain barrier via Ca(2)(+)-calcineurin signaling, J.Neurosci., 2012, 32, 8845-8854.[Crossref]
• [62] Wan W., Chen H., Li Y., The potential mechanisms of Abetareceptorfor advanced glycation end-products interactiondisrupting tight junctions of the blood-brain barrier inAlzheimer’s disease, Int. J. Neurosci., 2014, 124, 75-81.[Crossref]
• [63] Biron K.E., Dickstein D.L., Gopaul R., Jefferies W.A., Amyloidtriggers extensive cerebral angiogenesis causing blood brainbarrier permeability and hypervascularity in Alzheimer’sdisease, PLoS One, 2011, 6, e23789.
• [64] Pakrasi S., O’Brien J.T., Emission tomography in dementia,Nucl. Med. Commun., 2005, 26, 189-196.[Crossref]
• [65] Kang J.Y., Lee J.S., Kang H., Lee H.W., Kim Y.K., Jeon H.J., et al.,Regional cerebral blood flow abnormalities associated withapathy and depression in Alzheimer disease, Alzheimer Dis.Assoc. Disord., 2012, 26, 217-224.[Crossref]
• [66] Liu J., Zhu Y.S., Khan M.A., Brunk E., Martin-Cook K., WeinerM.F., et al., Global brain hypoperfusion and oxygenation inamnestic mild cognitive impairment, Alzheimers Dement.,2014, 10, 162-170.[Crossref]
• [67] Terada S., Sato S., Nagao S., Ikeda C., Shindo A., HayashiS., et al., Trail Making Test B and brain perfusion imagingin mild cognitive impairment and mild Alzheimer’s disease,Psychiatry Res., 2013, 213, 249-255.
• [68] Ongali B., Nicolakakis N., Lecrux C., Aboulkassim T.,Rosa-Neto P., Papadopoulos P., et al., Transgenic mice overexpressingAPP and transforming growth factor-beta1 featurecognitive and vascular hallmarks of Alzheimer’s disease, Am.J. Pathol., 2010, 177, 3071-3080.
• [69] Sochocka M., Koutsouraki E.S., Gasiorowski K., Leszek J,Vascular oxidative stress and mitochondrial failure in thepathobiology of Alzheimer’s disease: a new approach totherapy, CNS Neurol. Disord. Drug Targets, 2013, 12, 870-881.
• [70] Grammas P., Martinez J., Sanchez A., Yin X., Riley J., Gay D., etal., A new paradigm for the treatment of Alzheimer’s disease:targeting vascular activation, J. Alzheimers Dis., 2014, 40,619-30.
• [71] Yang S., Bae D., Kang H., Gwag B., Gho Y., Chae C.,Co-accumulation of vascular endothelial growth factorwith beta-amyloid in the brain of patients with Alzheimer’sdisease, Neurobiol. Aging, 2004, 25, 283-290.[Crossref]
• [72] Patel N.S., Mathura V.S., Bachmeier C., Beaulieu-AbdelahadD., Laporte V., Weeks O., et al., Alzheimer’s beta-amyloidpeptide blocks vascular endothelial growth factor mediatedsignaling via direct interaction with VEGFR-2, J. Neurochem.,2010, 112, 66-76.[Crossref]
• [73] Paris D., Townsend K., Quadros A., Humphrey J., Sun J., BremS., et al., Inhibition of angiogenesis by Abeta peptides,Angiogenesis, 2004, 7, 75-85.[Crossref]
• [74] Drachman D.A., The amyloid hypothesis, time to move on:Amyloid is the downstream result, not cause, of Alzheimer’sdisease, Alzheimers Dement., 2014, 10, 372-80.[Crossref]
• [75] Kuznetsova E., Schliebs R., β-Amyloid, cholinergictransmission, and cerebrovascular system -- a developmentalstudy in a mouse model of Alzheimer›s disease, Curr PharmDes., 2013, 19:6749-65.
• [76] Lee S.T., Chu K., Jung K.H., Park H.K., Kim D.H., Bahn J.J.,et al., Reduced circulating angiogenic cells in Alzheimerdisease, Neurology, 2009, 72, 1858-1863.[Crossref]
• [77] Safar M.M., Arab H.H., Rizk S.M., El-Maraghy S.A., Bonemarrow-derived endothelial progenitor cells protectagainst scopolamine-induced Alzheimer-like pathologicalaberrations, Mol. Neurobiol., (in press), DOI: 10.1007/s12035-014-9051-8.[Crossref]
• [78] Zlokovic B.V., The blood-brain barrier in health and chronicneurodegenerative disorders, Neuron, 2008, 57, 178-201.[Crossref]
• [79] Yan S.D., Bierhaus A., Nawroth P.P., Stern D.M., RAGE andAlzheimer’s disease: a progression factor for amyloid-betainducedcellular perturbation?, J. Alzheimers Dis., 2009, 16,833-843.[Crossref]
• [80] Shibata M., Yamada S., Kumar S.R., Calero M., Bading J.,Frangione B., et al., Clearance of Alzheimer’s amyloid-ss(1-40)peptide from brain by LDL receptor-related protein-1 at theblood-brain barrier, J. Clin. Invest., 2000, 106, 1489-1499.
• [81] Jaeger L.B., Dohgu S., Sultana R., Lynch J.L., Owen J.B.,Erickson M.A., et al., Lipopolysaccharide alters theblood-brain barrier transport of amyloid beta protein:a mechanism for inflammation in the progression ofAlzheimer’s disease, Brain Behav. Immun., 2009, 23, 507-517.[Crossref]
• [82] Attems J., Yamaguchi H., Saido T.C., Thal D.R., Capillary CAAand perivascular Abeta-deposition: two distinct features ofAlzheimer’s disease pathology, J. Neurol. Sci, 2010, 299,155-162.
• [83] Cummings B.J., Satou T., Head E., Milgram N.W., Cole G.M.,Savage M.J., et al., Diffuse plaques contain C-terminal Abeta 42 and not A beta 40: evidence from cats and dogs,Neurobiol. Aging, 1996, 17, 653-659.
• [84] Rajadas J., Sun W., Li H., Inayathullah M., Cereghetti D., TanA., et al., Enhanced Abeta(1-40) production in endothelialcells stimulated with fibrillar Abeta(1-42), PLoS One, 2013, 8,e58194.
• [85] Gomis M., Sobrino T., Ois A., Millan M., Rodriguez-CampelloA., Perez de la Ossa N., et al., Plasma beta-amyloid 1-40 isassociated with the diffuse small vessel disease subtype,Stroke, 2009, 40, 3197-3201.
• [86] Miao J., Xu F., Davis J., Otte-Holler I., Verbeek M.M., VanNostrand W.E., Cerebral microvascular amyloid betaprotein deposition induces vascular degeneration andneuroinflammation in transgenic mice expressing humanvasculotropic mutant amyloid beta precursor protein, Am. J.Pathol., 2005, 167, 505-515.
• [87] Kumar-Singh S., Pirici D., McGowan E., Serneels S., CeuterickC., Hardy J., et al., Dense-core plaques in Tg2576 and PSAPPmouse models of Alzheimer’s disease are centered on vesselwalls, Am. J. Pathol., 2005, 167, 527-543.
• [88] Veszelka S., Toth A.E., Walter F.R., Datki Z., Mozes E., Fulop L.,et al., Docosahexaenoic acid reduces amyloid-beta inducedtoxicity in cells of the neurovascular unit, J. Alzheimers Dis.,2013, 36, 487-501.
• [89] Liu R., Li J.Z., Song J.K., Zhou D., Huang C., Bai X.Y., etal., Pinocembrin improves cognition and protects theneurovascular unit in Alzheimer related deficits. NeurobiolAging, 2014, 35:1275-85.[Crossref]
• [90] Gentile M., Vecchione C., Maffei A., Aretini A., MarinoG., Poulet R., et al., Mechanisms of soluble beta-amyloidimpairment of endothelial function, J. Biol. Chem., 2004, 279,48135-48142.
• [91] Kouznetsova E., Klingner M., Sorger D., Sabri O., GrossmannU., Steinbach J., et al., Developmental and amyloid plaquerelatedchanges in cerebral cortical capillaries in transgenicTg2576 Alzheimer mice, Int. J. Dev. Neurosci., 2006, 24,187-193.
• [92] Deli M.A., Veszelka S., Csiszar B., Toth A., Kittel A., CseteM., et al., Protection of the blood-brain barrier by pentosanagainst amyloid-beta-induced toxicity, J. Alzheimers Dis.,2010, 22, 777-794.[Crossref]
• [93] Chisari M., Merlo S., Sortino M., Salomone S., Long-termincubation with beta-amyloid peptides impairs endotheliumdependentvasodilatation in isolated rat basilar artery,Pharmacol. Res., 2010, 61, 157-161.[Crossref]
• [94] Hsu M.J., Sheu J.R., Lin C.H., Shen M.Y., Hsu C.Y.,Mitochondrial mechanisms in amyloid beta peptide-inducedcerebrovascular degeneration, Biochim. Biophys. Acta, 2010,1800, 290-296.
• [95] Donnini S., Solito R., Cetti E., Corti F., Giachetti A., Carra S., etal., Abeta peptides accelerate the senescence of endothelialcells in vitro and in vivo, impairing angiogenesis, FASEB J.,2010, 24, 2385-2395.[Crossref]
• [96] Nakagawa K., Kiko T., Kuriwada S., Miyazawa T., Kimura F.,Miyazawa T., Amyloid beta induces adhesion of erythrocytesto endothelial cells and affects endothelial viability andfunctionality, Biosci. Biotechnol. Biochem., 2011, 75,2030-2033.[Crossref]
• [97] Chiu W.T., Shen S.C., Yang L.Y., Chow J.M., Wu C.Y., Chen Y.C.,Inhibition of HSP90-dependent telomerase activity in amyloidbeta-induced apoptosis of cerebral endothelial cells, J. Cell.Physiol., 2011, 226, 2041-2051.
• [98] Hayashi S., Sato N., Yamamoto A., Ikegame Y., NakashimaS., Ogihara T., et al., Alzheimer disease-associated peptide,amyloid beta40, inhibits vascular regeneration with inductionof endothelial autophagy, Arterioscler. Thromb. Vasc. Biol.,2009, 29, 1909-1915.[Crossref]
• [99] Hernandez-Guillamon M., Mawhirt S., Fossati S., Blais S.,Pares M., Penalba A., et al., Matrix metalloproteinase 2(MMP-2) degrades soluble vasculotropic amyloid-beta E22Qand L34V mutants, delaying their toxicity for human brainmicrovascular endothelial cells, J. Biol. Chem., 2010, 285,27144-27158.
• [100] Solito R., Corti F., Chen C.H., Mochly-Rosen D., Giachetti A.,Ziche M., et al., Mitochondrial aldehyde dehydrogenase-2activation prevents beta-amyloid-induced endothelial celldysfunction and restores angiogenesis, J. Cell Sci., 2013,126, 1952-1961.[Crossref]
• [101] Fossati S., Cam J., Meyerson J., Mezhericher E., Romero I.A.,Couraud P.O., et al., Differential activation of mitochondrialapoptotic pathways by vasculotropic amyloid-beta variantsin cells composing the cerebral vessel walls, FASEB J., 2010,24, 229-241.[Crossref]
• [102] Tai L.M., Holloway K.A., Male D.K., Loughlin A.J., RomeroI.A., Amyloid-beta-induced occludin down-regulation andincreased permeability in human brain endothelial cells ismediated by MAPK activation, J. Cell. Mol. Med., 2010, 14,1101-1112.
• [103] Kimura C., Oike M., Watanabe M., Ito Y., Proapoptotic nitricoxide production in amyloid beta protein-treated cerebralmicrovascular endothelial cells, Microcirculation, 2007, 14,89-97.[Crossref]
• [104] Fonseca A.C.R.G., Ferreiro E., Oliveira C.R., Cardoso S.M.,Pereira C.F., Activation of the endoplasmic reticulumstress response by the amyloid-beta 1-40 peptide in brainendothelial cells, Biochim. Biophys. Acta, 2013, 1832,2191-2203.
• [105] Fonseca A.C., Oliveira C.R., Pereira C.F., Cardoso S.M., Lossof proteostasis induced by amyloid beta peptide in brainendothelial cells, Biochim. Biophys. Acta, 2014, 1843,1150-1161.
• [106] Sheikh-Ali M., Sultan S., Alamir A.R., Haas M.J., MooradianA.D., Effects of antioxidants on glucose-induced oxidativestress and endoplasmic reticulum stress in endothelialcells, Diabetes Res. Clin. Pract., 2010, 87, 161-166.[Crossref]
• [107] Adachi T., Yasuda H., Nakamura S., Kamiya T., Hara H.,Hara H., et al., Endoplasmic reticulum stress inducesretinal endothelial permeability of extracellular-superoxidedismutase, Free Radic. Res., 2011, 45, 1083-1092.
• [108] Kito H., Yamazaki D., Ohya S., Yamamura H., Asai K.,Imaizumi Y., Up-regulation of K(ir)2.1 by ER stress facilitatescell death of brain capillary endothelial cells, Biochem.Biophys. Res. Commun., 2011, 411, 293-298.
• [109] Plácido A.I., Pereira C.M., Duarte A.I., Candeias E., CorreiaS.C., Santos R.X., et al., The role of endoplasmic reticulumin amyloid precursor protein processing and trafficking:Implication’s for Alzheimer’s disease, Biochim. Biophys.Acta, 2014, 1842, 1444-1453.[Crossref]
• [110] Lai E., Teodoro T., Volchuk A., Endoplasmic reticulumstress: signaling the unfolded protein response, Physiology(Bethesda), 2007, 22 193-201.[Crossref]
• [111] Ron D. and Walter P., Signal integration in the endoplasmicreticulum unfolded protein response. Nat. Rev. Mol. Cell.Biol., 2007, 8, 519-529.[Crossref]
• [112] Bertolotti A., Zhang Y., Hendershot L.M., Harding H.P., RonD. Dynamic interaction of BiP and ER stress transducers inthe unfolded-protein response, Nature Cell. Biol., 2000, 2,326-332.
• [113] Cox J.S., Shamu C.E., Walter P., Transcriptional induction ofgenes encoding endoplasmic reticulum resident proteinsrequires a transmembrane protein kinase, Cell, 1993,73,1197-1206.[Crossref]
• [114] Harding H.P., Zhang Y., Ron D., Protein translation andfolding are coupled by an endoplasmic-reticulum-residentkinase, Nature, 1999, 397, 271-274.
• [115] Harding H.P., Zhang Y., Zeng H., Novoa I., Lu P.D., Calfon M.,et al., An integrated stress response regulates amino acidmetabolism and resistance to oxidative stress, Mol. Cell.,2003, 11, 619-633.[Crossref]
• [116] Cullinan S.B., Diehl J.A., PERK-dependent activation of Nrf2contributes to redox homeostasis and cell survival followingendoplasmic reticulum stress, J. Biol. Chem., 2004, 279,20108-20117.
• [117] Haze K., Yoshida H., Yanagi H., Yura T., Mori K., Mammaliantranscription factor ATF6 is synthesized as a transmembraneprotein and activated by proteolysis in response toendoplasmic reticulum stress, Mol. Biol. Cell., 1999, 10,3787-3799.[Crossref]
• [118] Tsang K.Y., Chan D., Bateman J.F., Cheah K.S.E., In vivocellular adaptation to ER stress: survival strategies withdouble-edged consequences, J. Cell Sci., 2010, 123,2145-2154.[Crossref]
• [119] Decuypere J.P., Monaco G., Bultynck G., Missiaen L., DeSmedt H., Parys JB., The IP(3) receptor-mitochondriaconnection in apoptosis and autophagy, Biochim. Biophys.Acta, 2011, 1813, 1003-1013.
• [120] eegan S., Saveljeva S., Gorman A.M. and Samali A., Stressinducedself-cannibalism: on the regulation of autophagy byendoplasmic reticulum stress, Cell. Mol. Life Sci., 2013, 70,2425-2441.
• [121] Kim I., Xu W., Reed J.C., Cell death and endoplasmicreticulum stress: disease relevance and therapeuticopportunities, Nat. Rev. Drug Discov., 2008, 7. 1013-1030.
• [122] Candela P., Gosselet F., Saint-Pol J., Sevin E., BoucauM.C., Boulanger E., et al., Apical-to-basolateral transportof amyloid-beta peptides through blood-brain barriercells is mediated by the receptor for advanced glycationend-products and is restricted by P-glycoprotein, J.Alzheimers. Dis., 2010, 22, 849-859.[Crossref]
• [123] Pflanzner T., Janko M.C., Andre-Dohmen B., Reuss S.,Weggen S., Roebroek A.J., et al., LRP1 mediates bidirectionaltranscytosis of amyloid-beta across the blood-brain barrier,Neurobiol. Aging, 2011, 32, 2323.e1-11.
• [124] Plácido A.I., Oliveira C.R., Moreira P.I., Pereira C.M.,Enhanced amyloidogenic processing of amyloid precursorprotein and cell death under prolonged endoplasmicreticulum stress in brain endothelial cells, Mol. Neurobiol.,2015, 51, 571-590.[Crossref]
• [125] Deane R., Wu Z., Zlokovic B.V., RAGE (yin) versus LRP(yang) balance regulates Alzheimer amyloid beta-peptideclearance through transport across the blood-brain barrier,Stroke, 2004, 35, 2628-2631.[Crossref]
• [126] Fonseca A.C.R.G., Moreira P., Oliveira C.R., Cardoso S.M.,Pinton P., Pereira C.F., Amyloid-beta disrupts calciumand redox homeostasis in brain endothelial cells, Mol.Neurobiol., 2015, 51, 610-622.[Crossref]
• [127] Evangelista A.M., Thompson M.D., Weisbrod R.M., PimentalD.R., Tong X., Bolotina V.M., et al., Redox regulation ofSERCA2 is required for vascular endothelial growth factorinducedsignaling and endothelial cell migration, Antioxid.Redox Signal., 2012, 17, 1099-1108.[Crossref]
• [128] De Bock M., Wang N., Decrock E., Bol M., Gadicherla A.K.,Culot M., et al., Endothelial calcium dynamics, connexinchannels and blood-brain barrier function, Prog. Neurobiol.,2013, 108 1-20.[Crossref]
• [129] Glass C.A., Bates D.O., The role of endothelial cell Ca2+store release in the regulation of microvascular permeabilityin vivo, Exp. Physiol., 2004, 89, 343-351.[Crossref]
• [130] Bhatia R., Lin H., Lal R., Fresh and globular amyloid betaprotein (1-42) induces rapid cellular degeneration: evidencefor AbetaP channel-mediated cellular toxicity, FASEB J.,2000, 14, 1233-1243.
• [131] Cioffi D.L., Stevens T., Regulation of endothelial cell barrierfunction by store-operated calcium entry, Microcirculation,2006, 13, 709-723.[Crossref]
• [132] Gosselet F., Saint-Pol J., Candela P., Fenart L., Amyloid-betaPeptides, Alzheimer’s Disease and the Blood-brain Barrier,Curr. Alzheimer Res., 2013, 10, 1015-1033.[Crossref]
• [133] Pagani L., Eckert A., Amyloid-Beta interaction withmitochondria, Int. J. Alzheimers Dis., 2011, 925050.
• [134] Kim S., Sideris D.P., Sevier C.S., Kaiser C.A., BalancedEro1 activation and inactivation establishes ER redoxhomeostasis, J. Cell. Biol., 2012, 196, 713-725.
• [135] Galán M., Kassan M., Kadowitz P.J., Trebak M., BelmadaniS., Matrougui K., Mechanism of endoplasmic reticulumstress-induced vascular endothelial dysfunction, Biochim.Biophys. Acta, 2014, 1843, 1063-1075.
• [136] Tabas I., Ron D., Integrating the mechanisms of apoptosisinduced by endoplasmic reticulum stress, Nat. Cell Biol.,2011, 13, 184-190.[Crossref]
• [137] Contreras-Ferrat A., Lavandero S., Jaimovich E. and Klip A.,Calcium signaling in insulin action on striated muscle, CellCalcium, 2014, 56(5), 390-6.[Crossref]
• [138] Jornot L., Maechler P., Wollheim C.B., Junod A.F., Reactiveoxygen metabolites increase mitochondrial calcium inendothelial cells: implication of the Ca2+/Na+ exchanger, J.Cell Sci., 1999, 112, 1013-1022.
• [139] Galan C., Jardin I., Dionisio N., Salido G., Rosado J.A.,Role of oxidant scavengers in the prevention of Ca(2)+homeostasis disorders, Molecules, 2010, 15, 7167-7187.[Crossref]
• [140] Isenovic E., Soskic S., Dungen H.D., Dobutovic B., ElvisT., Simone I., et al., Regulation of endothelial nitric oxidesynthase in pathophysiological conditions, Cardiovasc.Hematol. Disord. Drug Targets, 2011, 11, 109-118.[Crossref]
• [141] Huppert J., Closhen D., Croxford A., White R., Kulig P.,Pietrowski E., et al., Cellular mechanisms of IL-17-inducedblood-brain barrier disruption, FASEB J, 2010, 24,1023-1034.[Crossref]
• [142] Feine I., Pinkas I., Salomon Y., Scherz A., Local oxidativestress expansion through endothelial cells--a key role forgap junction intercellular communication, PLoS One, 2012,7, e41633.
• [143] El Assar M., Angulo J. and Rodriguez-Manas L., Oxidativestress and vascular inflammation in aging, Free Radic BiolMed, 2013, 65 380-401.
• [144] Park L., Koizumi K., El Jamal S., Zhou P., Previti M.L.,Van Nostrand W.E., et al., Age-dependent neurovasculardysfunction and damage in a mouse model of cerebralamyloid angiopathy, Stroke, 2014, 45, 1815-1821.[Crossref]
• [145] Sanson M., Augé N., Vindis C., Muller C., Bando Y., ThiersJ.C., et al., Oxidized low-density lipoproteins triggerendoplasmic reticulum stress in vascular cells: preventionby oxygen-regulated protein 150 expression, Circ. Res.,2009, 104, 328-336.
• [146] Carvalho C., Katz P.S., Dutta S., Katakam P.V., MoreiraP.I., Busija D.W., Increased Susceptibility to Amyloid-betaToxicity in Rat Brain Microvascular Endothelial Cells underHyperglycemic Conditions, J. Alzheimers Dis., 2013, 38,75-83.
• [147] Mota S.I., Costa R.O., Ferreira I.L., Santana I., Caldeira G.L.,Padovano C., et al., Oxidative stress involving changes inNrf2 and ER stress in early stages of Alzheimer’s disease,Biochim. Biophys. Acta, 2015, 1852, 1428-1441.
• [148] Caldeira M.V., Salazar I.L., Curcio M., Canzoniero L.M.,Duarte C.B., Role of the ubiquitin-proteasome system inbrain ischemia: friend or foe?, Prog. Neurobiol., 2014, 112,50-69.[Crossref]
• [149] Nijholt D.A., de Graaf T.R., van Haastert E.S., Oliveira A.O.,Berkers C.R., Zwart R., et al., Endoplasmic reticulum stressactivates autophagy but not the proteasome in neuronalcells: implications for Alzheimer’s disease, Cell Death.Differ., 2011, 18, 1071-1081.[Crossref]
• [150] Song S., Lee H., Kam T., Tai M., Lee J., Noh J., et al., E2-25K/Hip-2 regulates caspase-12 in ER stress-mediated Abetaneurotoxicity, J. Cell Biol., 2008, 182, 675-684.
• [151] Tseng B.P., Green K.N., Chan J.L., Blurton-Jones M.,LaFerla F.M., Abeta inhibits the proteasome and enhancesamyloid and tau accumulation, Neurobiol. Aging, 2008, 29,1607-1618.[Crossref]
• [152] Keller J.N., Hanni K.B., Markesbery W.R., Impairedproteasome function in Alzheimer’s disease, J. Neurochem.,2000, 75, 436-439.
• [153] Levine B., Kroemer G., Autophagy in the pathogenesis ofdisease, Cell, 2008, 132, 27-42.
• [154] Silva D.F., Esteves A.R., Arduino D.M., Oliveira C.R., CardosoS.M., Amyloid-beta-induced mitochondrial dysfunctionimpairs the autophagic lysosomal pathway in a tubulindependent pathway, J. Alzheimers Dis., 2011, 26, 565-581.
• [155] Kurepa J., Wang S., Smalle J., The role of 26S proteasomedependentproteolysis in the formation and restructuringof microtubule networks, Plant Signal. Behav., 2012, 7,1289-1295.
• [156] Snigdha S., Smith E.D., Prieto G.A., Cotman C.W., Caspase-3activation as a bifurcation point between plasticity and celldeath, Neurosci. Bull., 2012, 28, 14-24.[Crossref]
• [157] Xue S., Cai X., Li W., Zhang Z., Dong W., Hui G., Elevatedplasma endothelial microparticles in Alzheimer’s disease,Dement. Geriatr. Cogn. Disord., 2012, 34, 174-180.[Crossref]
• [158] Verbeek M.M., de Waal R.M., Schipper J.J., Van NostrandW.E., Rapid degeneration of cultured human brain pericytesby amyloid beta protein, J. Neurochem., 1997, 68, 1135-1141.
• [159] Davis J., Cribbs D.H., Cotman C.W., Van Nostrand W.E.,Pathogenic amyloid beta-protein induces apoptosis incultured human cerebrovascular smooth muscle cells,Amyloid, 1999, 6, 157-164.[Crossref]
• [160] Bouvier N., Flinois J.P., Gilleron J., Sauvage F.L., LegendreC., Beaune P., et al., Cyclosporine triggers endoplasmicreticulum stress in endothelial cells: a role for endothelialphenotypic changes and death, Am. J. Physiol. RenalPhysiol., 2009, 296, F160-169.
• [161] Virrey J.J., Dong D., Stiles C., Patterson J.B., Pen L., Ni M., etal., Stress chaperone GRP78/BiP confers chemoresistanceto tumor-associated endothelial cells, Mol. Cancer Res.,2008, 6, 1268-1275.
• [162] Fassbender J.M., Saraswat-Ohri S., Myers S.A., GruenthalM.J., Benton R.L., Whittemore S.R., Deletion of endoplasmicreticulum stress-induced CHOP protects microvasculaturepost-spinal cord injury, Curr. Neurovasc. Res., 2012, 9,274-281.[Crossref]
• [163] Timmins J.M., Ozcan L., Seimon T.A., Li G., Malagelada C.,Backs J., et al., Calcium/calmodulin-dependent protein kinase II links ER stress with Fas and mitochondrialapoptosis pathways, J., Clin. Invest., 2009, 119, 2925-2941.[Crossref]
• [164] Yu J.T., Chang R.C., Tan L., Calcium dysregulation inAlzheimer’s disease: from mechanisms to therapeuticopportunities, Prog. Neurobiol., 2009, 89, 240-255.[Crossref]
• [165] Supnet C., Bezprozvanny I., The dysregulation ofintracellular calcium in Alzheimer disease, Cell Calcium,2010, 47, 183-189.[Crossref]
• [166] Grammas P., Botchlet T., Fugate R., Ball M.J., RoherA.E., Alzheimer disease amyloid proteins inhibit brainendothelial c

Identifiers

DOI

10.1515/ersc-2015-0005