- Email: [email protected]
219. Mechanisms of resistance to oxidative stress caused by amyloid beta
BIOLPSYCHL4TRY 1998;43:1s-133s
AbsenceEpilepsyor CAE).The results indicatedthat the mothers,but notthefathers,of the patientssharedin mildformsomeof the behavioral impairmentseenin the probands(Levav,1991).Thiswasevidentin tests of sustainedatlention(the ContinuousPerformanceTest or CPT,Rosvold et rd., 1956).This result is consistentwith prior research on the transmissionof the disorder,suggestingthatit is inheritedin the matemrd line. In the presentstudywe compared45 Canadianprobandswiththeir herdthyfirst-degreerelatives,as wellas 16healthycontrolpairsfromthe UnitedStates, in their performanceon neuropsychologicaltests. Attention, memoryand problem-solvingbehaviorwere studiedin order to evaluatepossiblefarniliaIaggregationof cognitivetraits in the disorder. In additionto CAE,weassessedproband-relativepairswithanotherform of generalizedepilepsy,JuvenileMyoclonicEpilepsy(JME),as well as proband-relativepairs with focal TemporalLobe Epilepsy(TLE).The results for the sustained attention measures obtained from the CPT supporttire view, that in generalizedseizure disordersthere is strong familialaggregationof traitsassociatedwithimpulsivity,inattentionand impairedaccuracy.The familial aggregationwas most pronouncedin JME,a disorderfor whicha genelocus,(6p21),has beerridentified.No familialaggregationof these traits was seen in TLE.
The Role of lntlammation and Oxidative Stress in the Pathophysiology of Alzheimer’s Disease Friday, May 29, 2:30 PM-5:00 PM, Location: Pier 7 Chairperson:Giulio Maria Pasinetti, Co-Chairperson:ChristianBehl 219. MECHANISMS OF RESISTANCE TO OXIDATIVE STRESS CAUSED BY AMYLOID BETA Y. Saga.ra & D. Schubert Departmentof CellularNeurobiology,The SrdkInstitutefor Biological Studies,La Jolla, CA 92037 Alzheimer’sdisease(AD)is characterized,in part,by neuronaldeathand the accumulationof amyloid~ protein(A~).Thereis ampleevidenceto suggest that A~ is the pathologicalculprit. A~-inducednerrrotoxicity involves oxidative stress, as supportedby the generationof reactive oxygenspecies (ROS),peroxidationof lipids, and protectiveeffects of antioxidrmts.The oxidativestress hypothesisproposesthat neuronsare graduallyand continuallystressed by the prooxidantA~, accumulate oxidationproducts,and ukimatelydie. Because understandinghow neuronsdefend themselvesagainst A13is potentiallytmeficial to devisingtreatmentsfor AD patients,pheochromocytoma(PC12)cells were culturedin the presenceof a toxicdoseof A~ for twomonthsandsurvivingcellsweresubclonedandcharacterized for altered phenotypesand gene expression.The resultingA~ resistant cells were also more resistant than the parental cells to oxidative stressors.A~ triggers the accumulationof ROS in the parental PC12 cells, but not in the resistantcells. The A13resistantcells have elevated levelsof catalaseandglutathioneperoxidase,butnot SOD.Additionally, dueto increasedexpressionlevelsof enzymesinvolvedin the -y-glutamyl cycle (y-glutamylcysteinesynthetase,glutathionereductase,glutathione S-transferases,and -y-glrrtamyltranspeptidase) the resistant cells have improvedmaintenanceof cellularglutathioneandresistanceto dkylating agents. These results indicate that coordinatedchanges in multiple antioxidantpathwaysare responsiblefor the resistanceto A~ -induced oxidativestress.Thus,up-regulationof cellularmechanismsthatremove ROSmay proteztcells from A13toxicity.
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220. ANTIOXIDANT STRATEGIES FOR NEUROPROTECTION: THE ROLE OF ESTROGENS AND NF-KB C. Behl Max-Planck-Instituteof Psychiatry-ClinicalInstitute,XraepelinStra8e 2-16,Munich,C&many80804 Oxidativestress-inducedneurorudcell degenerationhas beerrimplicated in a varietyof psychiatricand neurologicrddisordersincludingAlzheimer’s disease. Therefore, drugs that afford neuroprotection,are of primaryinterestin basicandpm-clinicalresearch.Antioxidantstrategies may be appliedat, at least, two differentlevels: Exogenousadditionof antioxidants:Neuronscan be protectedagainst oxidativestress-inducedbytheAlzheimer’sdiseaseassociatedamyloid~ protein,the excitatoryaminoacid glutamateand peroxidesby antioxidant includingvitaminE and melatordrr.In addition,differentsteroids haveantioxidantactivitiesdue to theirchemicalstructure.Oxidativecell degenerationin Irippocampalneuronscan he preventedby RU486andby the fernalesex hormoneestrogens.17-Pestradiol,its non-stereoisomer 17-a estradiolanddifferentestradiolderivativescanpreventintracellulw peroxideaccumulationand, ultimately,degenerationof neuronscaused by oxidation.The neuroprotectiveantioxidantactivity of estrogensis strictiydependenton the presenceof a hydroxylgroupin the C3position on the A-ringof a steroidmolecule,but is independenton an activation of estrogenreceptors. Inductionof an endogenousantioxidantstressresponse:The activityof intracellularantioxidantdefense systemscan be inducedby exogenous stimuli.Neuromdcells that are resistant against oxidativestress have increased activities of peroxide detoxifyingenzymes. Moreover, the activityof nucleartranscriptionfactorNF-xBis constitutivelyincreased. The suppressionof NF-KB’sactivity affects intracellularglutathione levels and reverses the resistance phenotypeof the cells. Therefore, NF-KBmight drive defense programs which carI effectively protect neuronsagainstoxidativestress. These two basic approachesmay help in the design of future drugs protectingneuronsagainstdiseaserelated oxidativeinsults.
221. CYCLOOXYGENASE-2 AND INFLAMMATION IN ALZHEIMER’S DISEASE L. Hoi, K. Kelley2, C. Blancol & G.M. Pasinettil’2 ‘Dept.Psychiatry2BrookdaleCenterfor MolecukuBiology,The MountSinai SchoolOf Medicine,New York,NY There is increasingevidencethat non-steroidaIanti-inflamrna tory drugs (iN.SAID) may attenuatethe progressionof neorodegeneratiorr in Alzbeimer’s disease (AD). We and others found nearly 2-fold elevationof irrmumoassayable COX-2contentinADfrontalcortexcomparedtonon-AD controls.The irumaseof COX-2inADbrain was prirnady Continedto neummdcellsin the greymatter.Basedon this evidenceandthe fact that overexpression of COX-2in neuroblastomacellspotentatesA~ mediated redoximpairmentwegeneratedatransgenicmousemodelinwhichneuronat overexpressiorr of human(h)-COX-2wasdrivenby a modifiedrat neuronspeciticenolmeOWE)pmrnoter.prelimimuystudiesfoundthat @mary neuronsderivedfromtransgenicmicewithneurrrnalCOX-2overexpmssion am more susceptibleto [email protected] resultsof these plannedstudieswillbehighlyusefulto the&signofanti-intlammatmy drug tials to slowthe rateof pmgmssionof AD.
AbsenceEpilepsyor CAE).The results indicatedthat the mothers,but notthefathers,of the patientssharedin mildformsomeof the behavioral impairmentseenin the probands(Levav,1991).Thiswasevidentin tests of sustainedatlention(the ContinuousPerformanceTest or CPT,Rosvold et rd., 1956).This result is consistentwith prior research on the transmissionof the disorder,suggestingthatit is inheritedin the matemrd line. In the presentstudywe compared45 Canadianprobandswiththeir herdthyfirst-degreerelatives,as wellas 16healthycontrolpairsfromthe UnitedStates, in their performanceon neuropsychologicaltests. Attention, memoryand problem-solvingbehaviorwere studiedin order to evaluatepossiblefarniliaIaggregationof cognitivetraits in the disorder. In additionto CAE,weassessedproband-relativepairswithanotherform of generalizedepilepsy,JuvenileMyoclonicEpilepsy(JME),as well as proband-relativepairs with focal TemporalLobe Epilepsy(TLE).The results for the sustained attention measures obtained from the CPT supporttire view, that in generalizedseizure disordersthere is strong familialaggregationof traitsassociatedwithimpulsivity,inattentionand impairedaccuracy.The familial aggregationwas most pronouncedin JME,a disorderfor whicha genelocus,(6p21),has beerridentified.No familialaggregationof these traits was seen in TLE.
The Role of lntlammation and Oxidative Stress in the Pathophysiology of Alzheimer’s Disease Friday, May 29, 2:30 PM-5:00 PM, Location: Pier 7 Chairperson:Giulio Maria Pasinetti, Co-Chairperson:ChristianBehl 219. MECHANISMS OF RESISTANCE TO OXIDATIVE STRESS CAUSED BY AMYLOID BETA Y. Saga.ra & D. Schubert Departmentof CellularNeurobiology,The SrdkInstitutefor Biological Studies,La Jolla, CA 92037 Alzheimer’sdisease(AD)is characterized,in part,by neuronaldeathand the accumulationof amyloid~ protein(A~).Thereis ampleevidenceto suggest that A~ is the pathologicalculprit. A~-inducednerrrotoxicity involves oxidative stress, as supportedby the generationof reactive oxygenspecies (ROS),peroxidationof lipids, and protectiveeffects of antioxidrmts.The oxidativestress hypothesisproposesthat neuronsare graduallyand continuallystressed by the prooxidantA~, accumulate oxidationproducts,and ukimatelydie. Because understandinghow neuronsdefend themselvesagainst A13is potentiallytmeficial to devisingtreatmentsfor AD patients,pheochromocytoma(PC12)cells were culturedin the presenceof a toxicdoseof A~ for twomonthsandsurvivingcellsweresubclonedandcharacterized for altered phenotypesand gene expression.The resultingA~ resistant cells were also more resistant than the parental cells to oxidative stressors.A~ triggers the accumulationof ROS in the parental PC12 cells, but not in the resistantcells. The A13resistantcells have elevated levelsof catalaseandglutathioneperoxidase,butnot SOD.Additionally, dueto increasedexpressionlevelsof enzymesinvolvedin the -y-glutamyl cycle (y-glutamylcysteinesynthetase,glutathionereductase,glutathione S-transferases,and -y-glrrtamyltranspeptidase) the resistant cells have improvedmaintenanceof cellularglutathioneandresistanceto dkylating agents. These results indicate that coordinatedchanges in multiple antioxidantpathwaysare responsiblefor the resistanceto A~ -induced oxidativestress.Thus,up-regulationof cellularmechanismsthatremove ROSmay proteztcells from A13toxicity.
65S
220. ANTIOXIDANT STRATEGIES FOR NEUROPROTECTION: THE ROLE OF ESTROGENS AND NF-KB C. Behl Max-Planck-Instituteof Psychiatry-ClinicalInstitute,XraepelinStra8e 2-16,Munich,C&many80804 Oxidativestress-inducedneurorudcell degenerationhas beerrimplicated in a varietyof psychiatricand neurologicrddisordersincludingAlzheimer’s disease. Therefore, drugs that afford neuroprotection,are of primaryinterestin basicandpm-clinicalresearch.Antioxidantstrategies may be appliedat, at least, two differentlevels: Exogenousadditionof antioxidants:Neuronscan be protectedagainst oxidativestress-inducedbytheAlzheimer’sdiseaseassociatedamyloid~ protein,the excitatoryaminoacid glutamateand peroxidesby antioxidant includingvitaminE and melatordrr.In addition,differentsteroids haveantioxidantactivitiesdue to theirchemicalstructure.Oxidativecell degenerationin Irippocampalneuronscan he preventedby RU486andby the fernalesex hormoneestrogens.17-Pestradiol,its non-stereoisomer 17-a estradiolanddifferentestradiolderivativescanpreventintracellulw peroxideaccumulationand, ultimately,degenerationof neuronscaused by oxidation.The neuroprotectiveantioxidantactivity of estrogensis strictiydependenton the presenceof a hydroxylgroupin the C3position on the A-ringof a steroidmolecule,but is independenton an activation of estrogenreceptors. Inductionof an endogenousantioxidantstressresponse:The activityof intracellularantioxidantdefense systemscan be inducedby exogenous stimuli.Neuromdcells that are resistant against oxidativestress have increased activities of peroxide detoxifyingenzymes. Moreover, the activityof nucleartranscriptionfactorNF-xBis constitutivelyincreased. The suppressionof NF-KB’sactivity affects intracellularglutathione levels and reverses the resistance phenotypeof the cells. Therefore, NF-KBmight drive defense programs which carI effectively protect neuronsagainstoxidativestress. These two basic approachesmay help in the design of future drugs protectingneuronsagainstdiseaserelated oxidativeinsults.
221. CYCLOOXYGENASE-2 AND INFLAMMATION IN ALZHEIMER’S DISEASE L. Hoi, K. Kelley2, C. Blancol & G.M. Pasinettil’2 ‘Dept.Psychiatry2BrookdaleCenterfor MolecukuBiology,The MountSinai SchoolOf Medicine,New York,NY There is increasingevidencethat non-steroidaIanti-inflamrna tory drugs (iN.SAID) may attenuatethe progressionof neorodegeneratiorr in Alzbeimer’s disease (AD). We and others found nearly 2-fold elevationof irrmumoassayable COX-2contentinADfrontalcortexcomparedtonon-AD controls.The irumaseof COX-2inADbrain was prirnady Continedto neummdcellsin the greymatter.Basedon this evidenceandthe fact that overexpression of COX-2in neuroblastomacellspotentatesA~ mediated redoximpairmentwegeneratedatransgenicmousemodelinwhichneuronat overexpressiorr of human(h)-COX-2wasdrivenby a modifiedrat neuronspeciticenolmeOWE)pmrnoter.prelimimuystudiesfoundthat @mary neuronsderivedfromtransgenicmicewithneurrrnalCOX-2overexpmssion am more susceptibleto [email protected] resultsof these plannedstudieswillbehighlyusefulto the&signofanti-intlammatmy drug tials to slowthe rateof pmgmssionof AD.