2025
diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease
Banerjee P, Wang Y, Carnevale L, Patel P, Raspur C, Tran N, Zhang X, Natarajan R, Roberts A, Baran P, Lipton S. diAcCA, a Pro-Drug for Carnosic Acid That Activates the Nrf2 Transcriptional Pathway, Shows Efficacy in the 5xFAD Transgenic Mouse Model of Alzheimer’s Disease. Antioxidants 2025, 14: 293. PMCID: PMC11939361, DOI: 10.3390/antiox14030293.Peer-Reviewed Original ResearchAlzheimer's diseaseNrf2 transcriptional pathwayTranscriptional pathwaysAmyloid plaque formationMouse model of Alzheimer's diseaseTransgenic mouse model of Alzheimer's diseaseModel of Alzheimer's diseaseAD transgenic miceCorrelated to cognitive declineNeuritic aggregatesTau tanglesAmyloid plaquesPhospho-tauCarnosic acidSynapse lossHuman ADPurified CATransgenic mouse modelPhenolic diterpenesAmyloidMicroglial inflammationPathwayPlaque formationTransgenic miceNrf2S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity
Zhang X, Vlkolinsky R, Wu C, Dolatabadi N, Scott H, Prikhodko O, Zhang A, Blanco M, Lang N, Piña-Crespo J, Nakamura T, Roberto M, Lipton S. S-Nitrosylation of CRTC1 in Alzheimer’s disease impairs CREB-dependent gene expression induced by neuronal activity. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2418179122. PMID: 40014571, PMCID: PMC11892585, DOI: 10.1073/pnas.2418179122.Peer-Reviewed Original ResearchConceptsActivity-dependent gene expressionGene expressionAlzheimer's diseaseCREB-dependent gene expressionS-nitrosylationNitric oxide (NO)-related speciesTargets of S-nitrosylationNeuronal activity-dependent gene expressionPathogenesis of ADDecreased neurite lengthIncreased neuronal cell deathNeuronal cell deathSynaptic plasticityTranscriptional pathwaysCell deathCRISPR/Cas9 techniqueTranscription coactivator 1AD modelLong-term memory formationIncreased S-nitrosylationLong-term potentiationTherapeutic targetExpressionNeurite lengthCerebrocortical neurons
2024
Using in vivo intact structure for system-wide quantitative analysis of changes in proteins
Son A, Kim H, Diedrich J, Bamberger C, McClatchy D, Lipton S, Yates J. Using in vivo intact structure for system-wide quantitative analysis of changes in proteins. Nature Communications 2024, 15: 9310. PMID: 39468068, PMCID: PMC11519357, DOI: 10.1038/s41467-024-53582-x.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseProtein footprinting methodGlobal expression profilingIn vivo conformationStructural alterations of proteinsCo-expressed proteinsMass spectrometry-based methodsAlterations of proteinsProteostasis dysfunctionSpectrometry-based methodsProtein misfoldingConformation of proteinsStructural changesLysine residuesDynamic structural changesBiological functionsProteomics experimentsDimethyl labelingExpression profilesProtein conformationConformational changesProteinIntact proteinDesign of therapeutic interventionsMeasuring dynamic structural changesSingle‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets
Ghatak S, Diedrich J, Talantova M, Bhadra N, Scott H, Sharma M, Albertolle M, Schork N, Yates J, Lipton S. Single‐Cell Patch‐Clamp/Proteomics of Human Alzheimer's Disease iPSC‐Derived Excitatory Neurons Versus Isogenic Wild‐Type Controls Suggests Novel Causation and Therapeutic Targets. Advanced Science 2024, 11: e2400545. PMID: 38773714, PMCID: PMC11304297, DOI: 10.1002/advs.202400545.Peer-Reviewed Original ResearchAbundance of individual proteinsIsogenic wild-type controlsSingle-cell (scHuman AD brainsWild-type controlsSingle-cellAlzheimer's diseaseMulticellular organismsSingle-cell physiologyAD brainTherapeutic targetIndividual proteinsProteomic informationGenetic mutationsProteinProteomicsProtein expressionHiPSC-neuronsExcitatory neuronsElectrophysiological statusDisease statesPhysiologyElectrophysiological dataNeuronsNeuronal levelMetabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons
Andreyev A, Yang H, Doulias P, Dolatabadi N, Zhang X, Luevanos M, Blanco M, Baal C, Putra I, Nakamura T, Ischiropoulos H, Tannenbaum S, Lipton S. Metabolic Bypass Rescues Aberrant S‐nitrosylation‐Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons. Advanced Science 2024, 11: 2306469. PMID: 38235614, PMCID: PMC10966553, DOI: 10.1002/advs.202306469.Peer-Reviewed Original ResearchTricarboxylic acidOxidative phosphorylationAlzheimer's diseaseSynapse lossSynaptic lossPathological correlate of cognitive declineHuman AD brainsTCA cycle inhibitionMetabolic flux experimentsAberrant S-nitrosylationPostmortem human AD brainIsogenic wild-typeAssociated with synaptic lossDysfunctional mitochondrial metabolismMitochondrial bioenergetic functionProtein S-nitrosylationModel of ADMitochondrial energy metabolismCell-permeable derivativeCorrelate of cognitive declineAD brainMitochondrial metabolismEnzyme functionHiPSC-based modelsBioenergetic function“Dark” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease: Mechanism and Potential Treatment
LIPTON S. “Dark” Pathways of Protein Transnitrosylation Injure Synapses in Alzheimer’s Disease: Mechanism and Potential Treatment. 2024, pl. DOI: 10.14869/toxpt.51.1.0_pl.Peer-Reviewed Original ResearchAlzheimer's diseaseDisruption of protein functionUbiquitin-protein hydrolaseS-nitrosylationS-nitrosylation reactionLoss of synapsesCorrelated to cognitive declineGuanosine triphosphataseMitochondrial fragmentationAD brainProtein functionAmyloid-betaAggregated proteinsProtein hydrolaseSynapse lossSynaptic lossBioenergetic compromiseSynaptic damageTransnitrosylation reactionsProteinUCH-L1Environmental factorsEnzymeAlzheimerCascade
2023
Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies
Ghatak S, Nakamura T, Lipton S. Aberrant protein S-nitrosylation contributes to hyperexcitability-induced synaptic damage in Alzheimer’s disease: Mechanistic insights and potential therapies. Frontiers In Neural Circuits 2023, 17: 1099467. PMID: 36817649, PMCID: PMC9932935, DOI: 10.3389/fncir.2023.1099467.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseSynaptic damageReactive oxygen speciesS-nitrosylation contributesNeuronal hyperactivitySynaptic lossSynapse lossSynaptic degenerationCommon causePotential therapyAD modelCognitive declineHyperexcitabilityDiseaseSingle neuronsActivity contributesMolecular changesProtein S-nitrosylationDeleterious effectsNeural network functionS-nitrosylationOxygen speciesEarly signaturesPatientsTherapy
2022
Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3
Yang H, Oh C, Amal H, Wishnok J, Lewis S, Schahrer E, Trudler D, Nakamura T, Tannenbaum S, Lipton S. Mechanistic insight into female predominance in Alzheimer’s disease based on aberrant protein S-nitrosylation of C3. Science Advances 2022, 8: eade0764. PMID: 36516243, PMCID: PMC9750152, DOI: 10.1126/sciadv.ade0764.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAD brainPostmortem Alzheimer's diseaseComplement component 3Sex-dependent mannerConsequent cognitive declineSynaptic phagocytosisΒ-estradiol levelsFemale predominanceAberrant protein S-nitrosylationSynaptic damageAD pathogenesisSNO proteinsCognitive declineProtein SDiseaseRobust alterationsBrainComponent 3Protein S-nitrosylationHuman brainS-nitrosylationS-nitrosoproteomePatientsPathogenesisHidden networks of aberrant protein transnitrosylation contribute to synapse loss in Alzheimer's disease
Lipton S. Hidden networks of aberrant protein transnitrosylation contribute to synapse loss in Alzheimer's disease. Free Radical Biology And Medicine 2022, 193: 171-176. PMID: 36243209, PMCID: PMC9875813, DOI: 10.1016/j.freeradbiomed.2022.10.272.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseParkinson's diseaseNitric oxideSoluble guanylate cyclaseFormation of peroxynitriteSynapse lossNeurocognitive disordersNeurological disordersDiseaseGuanylate cyclaseNeurodevelopmental disordersDisordersProtein S-nitrosylationSuperoxide anionTyrosine nitrationS-nitrosylationHIVS-nitrosationPathogenesisDementiaTowards development of disease-modifying therapy for Alzheimer's disease using redox chemical biology pathways
Lipton S. Towards development of disease-modifying therapy for Alzheimer's disease using redox chemical biology pathways. Current Opinion In Pharmacology 2022, 66: 102267. PMID: 35870288, PMCID: PMC9509422, DOI: 10.1016/j.coph.2022.102267.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseDisease-modifying therapiesPotential therapeutic efficacySevere side effectsPotential therapeutic targetCerebral organoid modelTranscription factor Nrf2Absence of diseaseNMDA typeGlutamate receptorsDisease processSide effectsTherapeutic targetTransgenic miceTherapeutic efficacyNeurodegenerative disordersNormal tissuesDiseaseFactor Nrf2Organoid modelsProtein S-nitrosylationS-nitrosylationProtein Keap1TherapyNrf2S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders
Kim K, Cho E, Eom J, Oh S, Nakamura T, Oh C, Lipton S, Kim Y. S-Nitrosylation of cathepsin B affects autophagic flux and accumulation of protein aggregates in neurodegenerative disorders. Cell Death & Differentiation 2022, 29: 2137-2150. PMID: 35462559, PMCID: PMC9613756, DOI: 10.1038/s41418-022-01004-0.Peer-Reviewed Original ResearchConceptsS-nitrosylationProtein aggregatesAutophagic fluxProtein S-nitrosylationBlocks autophagic fluxCathepsin BCaspase-dependent neuronal apoptosisPosttranslational modificationsProtease cathepsin BEnzymatic functionLysosomal protease cathepsin BCTSB activityChemical inhibitorsCA-074MeHuman AD brainsEnzymatic activityCysteineNeurodegenerative disordersPostmortem human AD brainTransgenic miceNeuronal apoptosisCTSBAccumulationAD pathogenesisAlzheimer's diseasePotential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer’s Disease, Parkinson’s Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome
Satoh T, Trudler D, Oh C, Lipton S. Potential Therapeutic Use of the Rosemary Diterpene Carnosic Acid for Alzheimer’s Disease, Parkinson’s Disease, and Long-COVID through NRF2 Activation to Counteract the NLRP3 Inflammasome. Antioxidants 2022, 11: 124. PMID: 35052628, PMCID: PMC8772720, DOI: 10.3390/antiox11010124.Peer-Reviewed Original ResearchSARS-CoV-2 infectionParkinson's diseaseAlzheimer's diseaseNeuroprotective effectsNLRP3 inflammasomeKeap1/Nrf2 transcriptional pathwayCarnosic acidAcute lung diseaseBlood-brain barrierChronic neurodegenerative diseasesNLRP3 inflammasome activationCoronavirus disease 2019Nrf2 transcriptional pathwayNLRP3 inflammasome activityPhase 2 enzyme inductionCOVID-19Potential therapeutic useEndovascular cellsBrain fogCytokine stormLong COVIDLung diseaseBrain parenchymaUnregulated inflammationDisease 2019
2021
Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases
Trudler D, Ghatak S, Lipton S. Emerging hiPSC Models for Drug Discovery in Neurodegenerative Diseases. International Journal Of Molecular Sciences 2021, 22: 8196. PMID: 34360966, PMCID: PMC8347370, DOI: 10.3390/ijms22158196.Peer-Reviewed Original ResearchConceptsAmyotrophic lateral sclerosisNeurodegenerative diseasesParkinson's diseaseAnimal modelsAlzheimer's diseaseEffective disease-modifying therapiesHuntington's diseaseDisease-modifying therapiesSeverity of symptomsHuman samplesHiPSC-derived neural cellsHealthy donorsEffective treatmentLateral sclerosisEconomic burdenHuman-induced pluripotent stem cell (hiPSC) technologyProgressive deteriorationNeural functionDiseaseHiPSC modelsNeural cellsPluripotent stem cell (iPSC) technologyDisease mechanismsPoor accessMillions of people
2009
Excitotoxicity in Neurodegenerative Disease
Haeberlein S, Lipton S. Excitotoxicity in Neurodegenerative Disease. 2009, 77-86. DOI: 10.1016/b978-008045046-9.00498-8.Peer-Reviewed Original ResearchHuman immunodeficiency virus-associated dementiaExcessive glutamate stimulationSpinal cord traumaMajor excitatory neurotransmitterAmyotrophic lateral sclerosisCord traumaExcitatory neurotransmitterGlutamate stimulationLateral sclerosisParkinson's diseaseTherapeutic interventionsAlzheimer's diseaseNeurodegenerative disordersDiseaseNeurodegenerative diseasesDownstream mechanismsHuntington's diseaseExcitotoxicityBrainSclerosisGlaucomaEpilepsyDementiaStrokeNeurotransmitters
2008
Clinically Tolerated Strategies for NMDA Receptor Antagonism
Vincent Chen H, Zhang D, Lipton S. Clinically Tolerated Strategies for NMDA Receptor Antagonism. The Receptors 2008, 327-361. DOI: 10.1007/978-1-59745-055-3_8.Peer-Reviewed Original ResearchExcessive NMDAR activityNMDAR activityClinical trialsGlutamate receptorsSide effectsNeurologic disordersNervous systemAcute hypoxic-ischemic brain injuryGeneralized inhibitionAlzheimer's diseaseSecond-generation memantine derivativesHypoxic-ischemic brain injuryPhase 3 clinical trialsExcessive NMDAR activationSevere neuropathic painExcitatory amino acidsGlutamate-mediated neurotoxicityGlutamate receptor subtypesChronic neurodegenerative diseasesSystemic side effectsMajor excitatory transmitterNormal functionNMDA receptor antagonismGreater neuroprotective propertiesCentral nervous system
2007
CHAPTER 25 Functional Characterization of Neurons
McKerchner S, Talantova M, Lipton S. CHAPTER 25 Functional Characterization of Neurons. 2007, 373-386. DOI: 10.1016/b978-012370465-8/50030-2.Peer-Reviewed Original ResearchCentral nervous systemAmyotrophic lateral sclerosisJuvenile-onset diseaseStem cell therapyNeuronal damageCurative treatmentElectrophysiological criteriaMacular degenerationLysosomal storage diseaseParkinson's diseaseLateral sclerosisOnset diseaseNervous systemAlzheimer's diseaseDiseaseCell therapySuch pathologyHuntington's diseaseStorage diseaseEarly childhoodTotal absenceLabeling cellsSclerosisTherapyInjury
2006
Mechanism‐Based Development of Memantine as a Therapeutic Agent in Treating Alzheimer's Disease and Other Neurologic Disorders: Low‐Affinity, Uncompetitive Antagonism with Fast Off‐Rate
Chen H, Lipton S. Mechanism‐Based Development of Memantine as a Therapeutic Agent in Treating Alzheimer's Disease and Other Neurologic Disorders: Low‐Affinity, Uncompetitive Antagonism with Fast Off‐Rate. 2006, 439-464. DOI: 10.1002/9780470131862.ch18.Peer-Reviewed Original Research
1998
■ REVIEW : Excitotoxicity, Free Radicals, Necrosis, and Apoptosis
Lipton S, Nicotera P. ■ REVIEW : Excitotoxicity, Free Radicals, Necrosis, and Apoptosis. The Neuroscientist 1998, 4: 345-352. DOI: 10.1177/107385849800400516.Peer-Reviewed Original ResearchNitric oxideMajor excitatory neurotransmitterCentral nervous systemFailure of neuronsFree radicalsNeuronal cell culturesActivation of proteasesNeuronal injuryAIDS dementiaNeuronal necrosisInitial insultExcitatory neurotransmitterNervous systemApoptotic death programAlzheimer's diseaseHuntington's diseaseDiseaseInsultExcitotoxicityMitochondrial membrane potentialNecrosisCell deathDeath programNeuronsApoptosis
1995
Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures.
Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton S. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proceedings Of The National Academy Of Sciences Of The United States Of America 1995, 92: 7162-7166. PMID: 7638161, PMCID: PMC41299, DOI: 10.1073/pnas.92.16.7162.Peer-Reviewed Original ResearchConceptsForm of neurotoxicityN-methyl-D-aspartate receptor-mediated neurotoxicityCell damageChronic neurologic disordersNeuronal cell damageCortical cell culturesFinal common pathwayNitric oxide/Superoxide dismutaseS-nitrosocysteineAIDS dementiaNecrotic cell damageFocal ischemiaAcute swellingInitial insultCortical neuronsNeurologic disordersAlzheimer's diseaseNitric oxideNMDANeurodegenerative diseasesHuntington's diseaseIntense exposureNeurotoxicityCommon pathway
1989
Growth Factors for Neuronal Survival and Process Regeneration: Implications in the Mammalian Central Nervous System
Lipton S. Growth Factors for Neuronal Survival and Process Regeneration: Implications in the Mammalian Central Nervous System. JAMA Neurology 1989, 46: 1241-1248. PMID: 2573331, DOI: 10.1001/archneur.1989.00520470113038.Peer-Reviewed Original ResearchConceptsNeuronal survivalClinical neurologistsMammalian central nervous systemCentral nervous systemPossible therapeutic approachesPotential clinical implicationsImmunodeficiency syndromeAxonal regenerationNeuronal transplantationNeurologic disordersTherapeutic approachesModulatory agentsNervous systemAlzheimer's diseaseClinical implicationsMammalian brainNerve growthNeuronal processesGrowth factorNeurologistsNumber of substancesDiseaseNeuronsProcess regenerationSurvival
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