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 changes
2023
Reply to: Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Oh C, Piña-Crespo J, Talantova M, Carnevale L, Stoneham C, Lewinski M, Guatelli J, Lipton S. Reply to: Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection. Nature Chemical Biology 2023, 19: 1306-1308. PMID: 37798355, DOI: 10.1038/s41589-023-01425-z.Peer-Reviewed Original ResearchS-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons
Doulias P, Yang H, Andreyev A, Dolatabadi N, Scott H, K Raspur C, Patel P, Nakamura T, Tannenbaum S, Ischiropoulos H, Lipton S. S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons. Cell Chemical Biology 2023, 30: 965-975.e6. PMID: 37478858, PMCID: PMC10530441, DOI: 10.1016/j.chembiol.2023.06.018.Peer-Reviewed Original ResearchConceptsTCA cycleLewy body dementiaAberrant S-nitrosylationMitochondrial metabolic dysfunctionTricarboxylic acid cyclePluripotent stem cellsMitochondrial energy metabolismParkinson's diseaseHiPSC-derived neuronsTCA enzymesMetabolic flux experimentsS-nitrosylationAcid cycleCell deathNeuronal cell deathΑ-ketoglutaratePostmortem human brainEnergy metabolismStem cellsLBD brainsDendritic lengthBioenergetic failureMetabolic dysfunctionSynaptic integrityPathophysiological relevanceApoptotic cell death in disease—Current understanding of the NCCD 2023
Vitale I, Pietrocola F, Guilbaud E, Aaronson S, Abrams J, Adam D, Agostini M, Agostinis P, Alnemri E, Altucci L, Amelio I, Andrews D, Aqeilan R, Arama E, Baehrecke E, Balachandran S, Bano D, Barlev N, Bartek J, Bazan N, Becker C, Bernassola F, Bertrand M, Bianchi M, Blagosklonny M, Blander J, Blandino G, Blomgren K, Borner C, Bortner C, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard R, Calin G, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan F, Chen G, Chen Q, Chen Y, Cheng E, Chipuk J, Cidlowski J, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz J, Czabotar P, D’Angiolella V, Daugaard M, Dawson T, Dawson V, De Maria R, De Strooper B, Debatin K, Deberardinis R, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon S, Dynlacht B, El-Deiry W, Elrod J, Engeland K, Fimia G, Galassi C, Ganini C, Garcia-Saez A, Garg A, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green D, Greene L, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick J, Haupt Y, He S, Heery D, Hengartner M, Hetz C, Hildeman D, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost P, Kanneganti T, Karin M, Kashkar H, Kaufmann T, Kelly G, Kepp O, Kimchi A, Kitsis R, Klionsky D, Kluck R, Krysko D, Kulms D, Kumar S, Lavandero S, Lavrik I, Lemasters J, Liccardi G, Linkermann A, Lipton S, Lockshin R, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine J, Martin S, Martinou J, Mastroberardino P, Medema J, Mehlen P, Meier P, Melino G, Melino S, Miao E, Moll U, Muñoz-Pinedo C, Murphy D, Niklison-Chirou M, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman J, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger J, Pentimalli F, Pereira D, Pervaiz S, Peter M, Pinton P, Porta G, Prehn J, Puthalakath H, Rabinovich G, Rajalingam K, Ravichandran K, Rehm M, Ricci J, Rizzuto R, Robinson N, Rodrigues C, Rotblat B, Rothlin C, Rubinsztein D, Rudel T, Rufini A, Ryan K, Sarosiek K, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica G, Silke J, Simon H, Sistigu A, Stephanou A, Stockwell B, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait S, Tang D, Tavernarakis N, Troy C, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden M, Vanderluit J, Verkhratsky A, Villunger A, von Karstedt S, Voss A, Vousden K, Vucic D, Vuri D, Wagner E, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang H, Zakeri Z, Zawacka-Pankau J, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease—Current understanding of the NCCD 2023. Cell Death & Differentiation 2023, 30: 1097-1154. PMID: 37100955, PMCID: PMC10130819, DOI: 10.1038/s41418-023-01153-w.Peer-Reviewed Original ResearchConceptsRegulated cell deathCell deathAdult tissue homeostasisMultiple human disordersApoptotic cell deathOrganismal developmentOrganismal homeostasisMolecular machineryContext of diseaseApoptotic apparatusMammalian systemsCaspase familyTissue homeostasisGenetic strategiesHuman disordersNomenclature CommitteeApoptosisHomeostasisMachineryOncogenesisProteaseCell lossActivationFamilyDeathPivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis
Okuda K, Nakahara K, Ito A, Iijima Y, Nomura R, Kumar A, Fujikawa K, Adachi K, Shimada Y, Fujio S, Yamamoto R, Takasugi N, Onuma K, Osaki M, Okada F, Ukegawa T, Takeuchi Y, Yasui N, Yamashita A, Marusawa H, Matsushita Y, Katagiri T, Shibata T, Uchida K, Niu S, Lang N, Nakamura T, Zhang K, Lipton S, Uehara T. Pivotal role for S-nitrosylation of DNA methyltransferase 3B in epigenetic regulation of tumorigenesis. Nature Communications 2023, 14: 621. PMID: 36739439, PMCID: PMC9899281, DOI: 10.1038/s41467-023-36232-6.Peer-Reviewed Original ResearchConceptsS-nitrosylationDNA methyltransferasesEnzymatic activityGene expressionDe novo DNA methylationNovo DNA methylationAberrant S-nitrosylationProtein S-nitrosylationDNA methyltransferase 3BDNMT enzymatic activityStructure-based virtual screeningEpigenetic regulationDNA methylationCysteine residuesMethyltransferase 3BVivo cancer modelsS-adenosylAberrant upregulationNeoplastic cell proliferationHuman colonic adenomasMethylationCyclin D2Cell proliferationTumor formationDNMT3BAberrant 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-nitrosationPathogenesisDementiaTargeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection
Oh C, Nakamura T, Beutler N, Zhang X, Piña-Crespo J, Talantova M, Ghatak S, Trudler D, Carnevale L, McKercher S, Bakowski M, Diedrich J, Roberts A, Woods A, Chi V, Gupta A, Rosenfeld M, Kearns F, Casalino L, Shaabani N, Liu H, Wilson I, Amaro R, Burton D, Yates J, Becker C, Rogers T, Chatterjee A, Lipton S. Targeted protein S-nitrosylation of ACE2 inhibits SARS-CoV-2 infection. Nature Chemical Biology 2022, 19: 275-283. PMID: 36175661, PMCID: PMC10127945, DOI: 10.1038/s41589-022-01149-6.Peer-Reviewed Original ResearchConceptsSARS-CoV-2 infectionViral entrySevere acute respiratory syndrome coronavirus 2Acute respiratory syndrome coronavirus 2Respiratory syndrome coronavirus 2Coronavirus disease 2019 (COVID-19) pandemicSyndrome coronavirus 2Prevention of infectionSARS-CoV-2 spike proteinDisease 2019 pandemicSpread of infectionCoronavirus 2Channel blockadeS-nitrosylationEnzyme 2Binding of ACE2InfectionSpike proteinACE2Envelope proteinProtein S-nitrosylationIon channelsNon-toxic compoundsNovel avenuesAngiotensinS-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 diseaseS-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia
Oh C, Dolatabadi N, Cieplak P, Diaz-Meco M, Moscat J, Nolan J, Nakamura T, Lipton S. S-Nitrosylation of p62 Inhibits Autophagic Flux to Promote α-Synuclein Secretion and Spread in Parkinson's Disease and Lewy Body Dementia. Journal Of Neuroscience 2022, 42: 3011-3024. PMID: 35169022, PMCID: PMC8985870, DOI: 10.1523/jneurosci.1508-21.2022.Peer-Reviewed Original ResearchConceptsLewy body dementiaParkinson's diseaseAutophagic fluxInhibits autophagic fluxΑ-synucleinPluripotent stem cell-derived neuronsStem cell-derived neuronsΑ-synuclein secretionS-nitrosylationCell-derived neuronsHuman postmortem brainProtein S-nitrosylationΑ-synuclein aggregationPostmortem brainsConsequent secretionPathologic pathwaysNervous systemAdaptor protein p62Autophagic inhibitionDysfunctional autophagyNeurodegenerative disordersDiseaseIndividual neuronsDementiaSecretion
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 peopleProtein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration
Nakamura T, Oh C, Zhang X, Lipton S. Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration. Free Radical Biology And Medicine 2021, 172: 562-577. PMID: 34224817, PMCID: PMC8579830, DOI: 10.1016/j.freeradbiomed.2021.07.002.Peer-Reviewed Original ResearchConceptsProtein misfoldingUbiquitin-proteasome systemCellular protein quality control machineryReactive oxygen speciesS-nitrosylationProtein quality control machineryQuality control machineryPost-translational modificationsNeurodegenerative diseasesProtein S-nitrosylationGenetic mutationsMost neurodegenerative diseasesMolecular chaperonesROS/RNSControl machineryLysosomal pathwayRare genetic mutationsMolecular mechanismsMolecular eventsMisfoldingMitochondrial dysfunctionTyrosine nitrationProteinOxygen speciesNeuronal demiseProtein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders
Nakamura T, Oh C, Zhang X, Tannenbaum S, Lipton S. Protein Transnitrosylation Signaling Networks Contribute to Inflammaging and Neurodegenerative Disorders. Antioxidants & Redox Signaling 2021, 35: 531-550. PMID: 33957758, PMCID: PMC8388249, DOI: 10.1089/ars.2021.0081.Peer-Reviewed Original ResearchConceptsRelated reactive nitrogen speciesS-nitrosylationRedox-based posttranslational modificationProtein S-nitrosylationGlyceraldehyde-3-phosphate dehydrogenaseInhibitor of apoptosisThiol-containing proteinsNeurodegenerative diseasesSignaling networksPosttranslational modificationsReactive nitrogen speciesTransnitrosylation reactionsNuclear proteinsUnderstanding of agingCysteine thiolsTransnitrosylationBiochemical pathwaysChemical biologyMechanisms of diseaseProteinCaspase-3Nitrogen speciesUCH-L1Neurodegenerative disordersPhysiological concentrationsMetformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation
Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother T, Tourtellotte W, Zhang Y, Aleman-Muench G, Lewis G, Chen W, Kang S, Luevanos M, Trudler D, Lipton S, Soroosh P, Teijaro J, de la Torre J, Arditi M, Karin M, Sanchez-Lopez E. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021, 54: 1463-1477.e11. PMID: 34115964, PMCID: PMC8189765, DOI: 10.1016/j.immuni.2021.05.004.Peer-Reviewed Original ResearchConceptsAcute respiratory distress syndromeInflammasome activationSARS-CoV-2-induced acute respiratory distress syndromeMyeloid-specific ablationSevere COVID-19Anti-diabetic medicationsAnti-inflammatory effectsRespiratory distress syndromeIL-6 secretionNLRP3 inflammasome activationHigh mortality rateCOVID-19 lungsInhibition of ATPDistress syndromePulmonary inflammationIL-6Inflammatory conditionsMetformin inhibitionMetformin inhibitsARDS severityNF-κBNLRP3 ligandsMortality rateAlveolar macrophagesDNA synthesisTCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use
Doulias P, Nakamura T, Scott H, McKercher S, Sultan A, Deal A, Albertolle M, Ischiropoulos H, Lipton S. TCA cycle metabolic compromise due to an aberrant S-nitrosoproteome in HIV-associated neurocognitive disorder with methamphetamine use. Journal Of NeuroVirology 2021, 27: 367-378. PMID: 33876414, PMCID: PMC8477648, DOI: 10.1007/s13365-021-00970-4.Peer-Reviewed Original ResearchConceptsNeurocognitive disordersMeth usePathogenesis of HIVHuman postmortem brainAberrant protein S-nitrosylationCNS pathologyControl brainsSynaptic damageS-nitrosylationHIV-1Metabolic compromisePostmortem brainsMethamphetamine useNitric oxideDrug abuseRedox stressNitrosative stressBrainHIVProtein S-nitrosylationDisordersS-nitrosoproteomeSystematic inhibitionTCA cycle enzymesPathogenesisSoluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia
Trudler D, Nazor K, Eisele Y, Grabauskas T, Dolatabadi N, Parker J, Sultan A, Zhong Z, Goodwin M, Levites Y, Golde T, Kelly J, Sierks M, Schork N, Karin M, Ambasudhan R, Lipton S. Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2025847118. PMID: 33833060, PMCID: PMC8054017, DOI: 10.1073/pnas.2025847118.Peer-Reviewed Original ResearchConceptsHuman microgliaLike receptor family pyrinFibrillar αSynA9 dopaminergic neuronsInterleukin-1β secretionCaspase-1 activationMicroglial activationFamily pyrinAntibody therapyNeuronal deathParkinson's diseaseMicrogliaMouse brainΑ-synucleinDual stimulationMitochondrial damageΑSynAntibodiesInflammationNLRP3Cognate antibodiesHuman brainDiseaseNeuronsStem cellsS-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD
Pirie E, Oh C, Zhang X, Han X, Cieplak P, Scott H, Deal A, Ghatak S, Martinez F, Yeo G, Yates J, Nakamura T, Lipton S. S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2021368118. PMID: 33692125, PMCID: PMC7980404, DOI: 10.1073/pnas.2021368118.Peer-Reviewed Original ResearchConceptsProtein misfolding/aggregationCell spreadMisfolding/aggregationRNA-binding activityOligomerization/aggregationHuman-induced pluripotent stem cellsProtein TDP-43Pluripotent stem cellsALS/FTDTDP-43 aggregationTDP-43Cognate proteinProtein aggregationS-nitrosylationRare genetic mutationsCell-based modelFTD disordersAmyotrophic lateral sclerosisAbsence of mutationsTriggers aggregationStem cellsGenetic mutationsDisulfide linkagesNitrosative stressNeurodegenerative disordersα-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss
Trudler D, Sanz-Blasco S, Eisele Y, Ghatak S, Bodhinathan K, Akhtar M, Lynch W, Piña-Crespo J, Talantova M, Kelly J, Lipton S. α-Synuclein Oligomers Induce Glutamate Release from Astrocytes and Excessive Extrasynaptic NMDAR Activity in Neurons, Thus Contributing to Synapse Loss. Journal Of Neuroscience 2021, 41: 2264-2273. PMID: 33483428, PMCID: PMC8018774, DOI: 10.1523/jneurosci.1871-20.2020.Peer-Reviewed Original ResearchConceptsLewy body dementiaExtrasynaptic NMDA receptorsSynaptic damageParkinson's diseaseNeuronal lossLewy bodiesNMDAR activityDisease progressionΑSyn oligomersPotential disease-modifying interventionsNeurodegenerative diseasesΑ-synucleinExtrasynaptic NMDAR activitySynaptic NMDAR activityDisease-modifying interventionsPatch-clamp recordingsMajor neuropathological characteristicsSynaptic lossAstrocytic glutamateGlutamate releaseSynapse lossSpine lossExtrasynaptic NMDARsFemale miceHippocampal slices
2019
Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls
Ghatak S, Dolatabadi N, Trudler D, Zhang X, Wu Y, Mohata M, Ambasudhan R, Talantova M, Lipton S. Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. ELife 2019, 8: e50333. PMID: 31782729, PMCID: PMC6905854, DOI: 10.7554/elife.50333.Peer-Reviewed Original ResearchConceptsDisease brainNeuronal culturesHuman Alzheimer's disease brainCerebral organoidsAD-related mutationsHiPSC-derived neuronsTransgenic AD miceInhibitory synaptic activityMechanisms of hyperexcitabilityAlzheimer's disease brainAberrant electrical activitySodium current densityAD micePathophysiological correlatesSynaptic dysfunctionAD pathophysiologyExcessive excitabilitySynaptic activityObserved hyperexcitabilityCognitive declineBursting activityHyperexcitabilityPresenilin 1Electrical activityNeurite length