2025
Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases
Johnson E, Nowar R, Viola K, Huang W, Zhou S, Bicca M, Zhu W, Kranz D, Klein W, Silverman R. Inhibition of amyloid beta oligomer accumulation by NU-9: A unifying mechanism for the treatment of neurodegenerative diseases. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2402117122. PMID: 40030015, PMCID: PMC11912461, DOI: 10.1073/pnas.2402117122.Peer-Reviewed Original ResearchConceptsProtein aggregationNeurodegenerative diseasesMechanisms of protein aggregationAmyloid-beta oligomersAlzheimer's disease neurodegenerationEndolysosomal traffickingBeta oligomersOligomer accumulationTreatment of neurodegenerative diseasesTDP-43Disease neurodegenerationPeptide aggregationLysosome-dependentCathepsin LProteinHippocampal neuronsPathological accumulationQuantitative assayTraffickingCellular mechanismsCathepsin BBlock neurodegenerationImmunofluorescence imagingPathogenic mechanismsNeurodegeneration
2024
Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice
Kang R, Kim K, Jung Y, Choi S, Lee C, Im G, Shin M, Ryu K, Choi S, Yang E, Shin W, Lee S, Lee S, Papadopoulos Z, Ahn J, Koh G, Kipnis J, Kang H, Kim H, Cho W, Park S, Kim S, Kim E. Loss of Katnal2 leads to ependymal ciliary hyperfunction and autism-related phenotypes in mice. PLOS Biology 2024, 22: e3002596. PMID: 38718086, PMCID: PMC11104772, DOI: 10.1371/journal.pbio.3002596.Peer-Reviewed Original ResearchConceptsAutism spectrum disorderBehavioral phenotypesASD-relatedSocial communication deficitsAutism-related phenotypesEnlarged lateral ventriclesProgressive ventricular enlargementCommunication deficitsSpectrum disorderSynaptic deficitsEnlargement of brain ventriclesTranscriptomic changesMicrotubule-regulatory proteinsGenes down-regulatedBrain ventriclesVentricular enlargementLateral ventricleDeficitsHippocampal neuronsMotile ciliaKATNAL2Potential treatmentDown-regulationCiliary functionEpendymal cellsMonozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission
Stern S, Zhang L, Wang M, Wright R, Rosh I, Hussein Y, Stern T, Choudhary A, Tripathi U, Reed P, Sadis H, Nayak R, Shemen A, Agarwal K, Cordeiro D, Peles D, Hang Y, Mendes A, Baul T, Roth J, Coorapati S, Boks M, McCombie W, Hulshoff Pol H, Brennand K, Réthelyi J, Kahn R, Marchetto M, Gage F. Monozygotic twins discordant for schizophrenia differ in maturation and synaptic transmission. Molecular Psychiatry 2024, 29: 3208-3222. PMID: 38704507, PMCID: PMC11449799, DOI: 10.1038/s41380-024-02561-1.Peer-Reviewed Original ResearchCo-TwinSchizophrenia patientsMonozygotic twinsHippocampal synaptic deficitsHealthy twinsSynapse-related genesDepressive disorderPsychiatric disordersSchizophreniaControl twinsTwin pairsSynaptic activitySynaptic deficitsTwin siblingsNeurophysiological abnormalitiesGroup of patientsSynaptic transmissionDiscordant twinsDisordersHippocampal neuronsNeuronsReprogrammed iPSCsIPSC modelsPatientsSiblings
2023
Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596
Acker B, Badescu V, Berkenpas M, Groppi V, Hajós M, Higdon N, Hurst R, Jacobsen E, Margolis B, McWhorter W, Myers J, Piotrowski D, Rogers B, Sarapa D, Vetman T, Walker D, Wall T, Wilhite D, Wishka D, Xu W, Yates K. Positive allosteric modulators of the α7 nicotinic acetylcholine receptor: SAR investigation around PNU-120596. Bioorganic & Medicinal Chemistry Letters 2023, 93: 129433. PMID: 37557923, DOI: 10.1016/j.bmcl.2023.129433.Peer-Reviewed Original ResearchConceptsΑ7 nicotinic acetylcholine receptorNicotinic acetylcholine receptorsPositive allosteric modulatorsAcetylcholine receptorsPNU-120596Powerful positive allosteric modulatorAllosteric modulatorsRat hippocampal neuronsPresence of acetylcholineDose-dependent mannerLigand-gated ion channelsCerebral cortexRat modelHippocampal neuronsSynaptic transmissionSensory gatingReceptorsEnhanced potencyIon channelsUnique biologyInitial structure-activity relationshipsSAR investigationCompound 16Structure-activity relationshipsThalamus
2022
The Role of Alpha-Tocotrienol during Development of Primary Hippocampal Neurons
Park H, Crowe-White K, Ciesla L, Bannerman S, Scott M, Davis A, Adhikari B, Burnett G, Broman K, Ferdous K, Lackey K, Lickznerski P, Jonas E. The Role of Alpha-Tocotrienol during Development of Primary Hippocampal Neurons. Current Developments In Nutrition 2022, 6: 800. PMCID: PMC9194400, DOI: 10.1093/cdn/nzac064.019.Peer-Reviewed Original ResearchPrimary hippocampal neuronsHippocampal neuronsPrimary rat hippocampal neuronsRat hippocampal neuronsAlpha-tocotrienolProtein levelsBcl-xLMitochondrial functionMitochondrial superoxide levelsNeuroprotective propertiesNeuronal ATPSholl analysisNeurobasal mediumNeurite complexityB cellsVitamin ENeuron developmentNeuronsBeneficial effectsSuperoxide levelsNeuronal growthConditioned mediaNeurite morphologyIntracellular ATPMitochondrial superoxideAlpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL
Park HA, Crowe-White KM, Ciesla L, Scott M, Bannerman S, Davis AU, Adhikari B, Burnett G, Broman K, Ferdous KA, Lackey KH, Licznerski P, Jonas EA. Alpha-tocotrienol enhances arborization of primary hippocampal neurons via upregulation of Bcl-xL. Nutrition Research 2022, 101: 31-42. PMID: 35366596, PMCID: PMC9081260, DOI: 10.1016/j.nutres.2022.02.007.Peer-Reviewed Original ResearchConceptsPrimary hippocampal neuronsControl neuronsHippocampal neuronsAlpha-tocotrienolBcl-xLVitamin E familyCerebral ischemiaNeuronal viabilityMature neuronsB cellsNeurite complexityNeuronal functionMitochondrial energy productionBrain developmentCentral mechanismsNeuronsBeneficial effectsOxidative stressBcl-xL upregulationProtein levelsNeurite branchingTreatmentE familyATP levelsNeurite outgrowthHippocampal acetylcholine modulates stress-related behaviors independent of specific cholinergic inputs
Mineur YS, Mose TN, Vanopdenbosch L, Etherington IM, Ogbejesi C, Islam A, Pineda CM, Crouse RB, Zhou W, Thompson DC, Bentham MP, Picciotto MR. Hippocampal acetylcholine modulates stress-related behaviors independent of specific cholinergic inputs. Molecular Psychiatry 2022, 27: 1829-1838. PMID: 34997190, PMCID: PMC9106825, DOI: 10.1038/s41380-021-01404-7.Peer-Reviewed Original ResearchConceptsStress-related behaviorsCholinergic inputMedial septum/diagonal bandBehavioral effectsBrain ACh levelsChAT-positive neuronsSelective chemogenetic activationMuscarinic ACh receptorsDepression-like symptomsSignificant behavioral effectsHippocampal acetylcholineMaladaptive behavioral responsesAntidepressant effectsCholinergic neuronsACh releaseChemogenetic activationChemogenetic inhibitionCholinergic antagonistsLocal infusionAcetylcholine levelsACh levelsDiagonal bandACh receptorsHippocampal neuronsPharmacological approaches
2021
Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss
Richard EM, Bakhtiari S, Marsh APL, Kaiyrzhanov R, Wagner M, Shetty S, Pagnozzi A, Nordlie SM, Guida BS, Cornejo P, Magee H, Liu J, Norton BY, Webster RI, Worgan L, Hakonarson H, Li J, Guo Y, Jain M, Blesson A, Rodan LH, Abbott MA, Comi A, Cohen JS, Alhaddad B, Meitinger T, Lenz D, Ziegler A, Kotzaeridou U, Brunet T, Chassevent A, Smith-Hicks C, Ekstein J, Weiden T, Hahn A, Zharkinbekova N, Turnpenny P, Tucci A, Yelton M, Horvath R, Gungor S, Hiz S, Oktay Y, Lochmuller H, Zollino M, Morleo M, Marangi G, Nigro V, Torella A, Pinelli M, Amenta S, Husain RA, Grossmann B, Rapp M, Steen C, Marquardt I, Grimmel M, Grasshoff U, Korenke GC, Owczarek-Lipska M, Neidhardt J, Radio FC, Mancini C, Claps Sepulveda DJ, McWalter K, Begtrup A, Crunk A, Guillen Sacoto MJ, Person R, Schnur RE, Mancardi MM, Kreuder F, Striano P, Zara F, Chung WK, Marks WA, van Eyk CL, Webber DL, Corbett MA, Harper K, Berry JG, MacLennan AH, Gecz J, Tartaglia M, Salpietro V, Christodoulou J, Kaslin J, Padilla-Lopez S, Bilguvar K, Munchau A, Ahmed ZM, Hufnagel RB, Fahey MC, Maroofian R, Houlden H, Sticht H, Mane SM, Rad A, Vona B, Jin SC, Haack TB, Makowski C, Hirsch Y, Riazuddin S, Kruer MC. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss. American Journal Of Human Genetics 2021, 108: 2006-2016. PMID: 34626583, PMCID: PMC8546233, DOI: 10.1016/j.ajhg.2021.08.003.Peer-Reviewed Original ResearchConceptsSensorineural hearing lossCerebral palsyHearing lossBi-allelic variantsInner earRodent inner earDevelopmental delay/intellectual disabilityThin corpus callosumGlial cell nucleiIntellectual disabilityRat hippocampal neuronsWhite matter volumeNeurosensory hair cellsPeriventricular leukomalaciaQuantitative volumetryCerebral volumeCorpus callosumHippocampal neuronsMatter volumeReceptor functionBrain imagingHair cellsProminent expressionNeurodevelopmental phenotypesAffected individualsSelective Overexpression of Collybistin in Mouse Hippocampal Pyramidal Cells Enhances GABAergic Neurotransmission and Protects against PTZ-Induced Seizures
George S, James S, De Blas A. Selective Overexpression of Collybistin in Mouse Hippocampal Pyramidal Cells Enhances GABAergic Neurotransmission and Protects against PTZ-Induced Seizures. ENeuro 2021, 8: eneuro.0561-20.2021. PMID: 34083383, PMCID: PMC8281261, DOI: 10.1523/eneuro.0561-20.2021.Peer-Reviewed Original ResearchConceptsHippocampal pyramidal cellsPyramidal cellsPyramidal neuronsAdeno-associated virusGABAergic synaptic transmissionCortical pyramidal neuronsHippocampal pyramidal neuronsMouse hippocampal pyramidal cellsCultured hippocampal neuronsAbsence of gephyrinCre-dependent mannerGABAergic neurotransmissionCre miceInhibitory neurotransmissionHippocampal interneuronsInhibitory postsynapsesInhibitory synapsesHippocampal neuronsSynaptic transmissionTarget neuronsPostsynaptic sitesBrain regionsMice resultsSelective overexpressionGlycinergic postsynapsesVitamin E Improves Neurite Complexity by Enhancing Mitochondrial Function
Park H, Crowe-White K, Davis A, Bannerman S, Burnett G, Scott M, Broman K, Lackey K, Licznerski P, Jonas E. Vitamin E Improves Neurite Complexity by Enhancing Mitochondrial Function. Current Developments In Nutrition 2021, 5: 5140915. PMCID: PMC8181647, DOI: 10.1093/cdn/nzab049_028.Peer-Reviewed Original ResearchPost-translational cleavagePrimary hippocampal neuronsBcl-xLMitochondrial functionHippocampal neuronsNeurite complexityNeurite outgrowthOxidative stressProtein levelsPotential therapeutic roleProtein Bcl-xLVitamin E familyATP/ADP ratioNormal physiological developmentNovel functionBrain injuryTherapeutic roleReal-time PCRSholl analysisNew synapsesNeurobasal mediumATP productionNeurite injuryControl groupVitamin EAstroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy
Sandhu MRS, Gruenbaum BF, Gruenbaum SE, Dhaher R, Deshpande K, Funaro MC, Lee TW, Zaveri HP, Eid T. Astroglial Glutamine Synthetase and the Pathogenesis of Mesial Temporal Lobe Epilepsy. Frontiers In Neurology 2021, 12: 665334. PMID: 33927688, PMCID: PMC8078591, DOI: 10.3389/fneur.2021.665334.Peer-Reviewed Original ResearchMesial temporal lobe epilepsyAstroglial glutamine synthetaseTemporal lobe epilepsyLobe epilepsyIntractable mesial temporal lobe epilepsyAstrocytic glutamine synthetaseDepressive-like featuresPathogenesis of epilepsyType of epilepsyDiscrete brain regionsNeocortical epilepsyHippocampal neuronsEpilepsyBrain regionsGlutamate-ammonia ligaseLaboratory animalsPathogenesisPossible roleExperimental inhibitionGlutamine synthetaseEnzyme glutamine synthetaseDysfunctionSeizuresAstrocytesSyndromeAbl2:Cortactin Interactions Regulate Dendritic Spine Stability via Control of a Stable Filamentous Actin Pool
Shaw JE, Kilander MBC, Lin YC, Koleske AJ. Abl2:Cortactin Interactions Regulate Dendritic Spine Stability via Control of a Stable Filamentous Actin Pool. Journal Of Neuroscience 2021, 41: 3068-3081. PMID: 33622779, PMCID: PMC8026353, DOI: 10.1523/jneurosci.2472-20.2021.Peer-Reviewed Original ResearchConceptsDendritic spine stabilityDendritic spinesSpine stabilityTonic increaseSubset of spinesSexes of miceMost excitatory synapsesCortactin interactionsGluN2B levelsSpine densitySpine lossArg nonreceptor tyrosine kinaseKinetically distinct poolsExcitatory synapsesHippocampal neuronsSynaptic activitySpine enlargementSpineSpine sizeSpine actinActivity-dependent spine enlargementSpine shapeStructural plasticityDistinct poolsTyrosine kinaseSymmetrical arrangement of proteins under release-ready vesicles in presynaptic terminals
Radhakrishnan A, Li X, Grushin K, Krishnakumar SS, Liu J, Rothman JE. Symmetrical arrangement of proteins under release-ready vesicles in presynaptic terminals. Proceedings Of The National Academy Of Sciences Of The United States Of America 2021, 118: e2024029118. PMID: 33468631, PMCID: PMC7865176, DOI: 10.1073/pnas.2024029118.Peer-Reviewed Original ResearchConceptsPlasma membraneSynaptic vesiclesSV fusionRelease-ready vesiclesFusion machinerySingle SNAREpinSV releaseExocytosis machineryMolecular eventsNative conditionsProtein componentsCultured hippocampal neuronsPriming reactionPresynaptic CaVesiclesFundamental processesProtein densityProtein massRelease of neurotransmittersNeurotransmitter releaseMachineryPresynaptic terminalsReleasable poolHippocampal neuronsVariable number
2020
Roles of Vitamin E in Energy Metabolism During Neurite Outgrowth
Stratton Z, Davis A, Jonas E, Crowe-White K, Park H. Roles of Vitamin E in Energy Metabolism During Neurite Outgrowth. Current Developments In Nutrition 2020, 4: nzaa057_051. PMCID: PMC7259054, DOI: 10.1093/cdn/nzaa057_051.Peer-Reviewed Original ResearchPrimary hippocampal neuronsBrain injuryHippocampal neuronsControl groupNeurite outgrowthNeuronal energy metabolismMaintenance of synapsesVitamin E familyEnergy metabolismNeurite lossNeurobasal mediumVitamin EAlpha-tocotrienolBrain developmentNeuronsOxidative stressNeurite growthBranched neuritesCentral targetMitochondrial inner membrane potentialE familyATP levelsTreatmentNeuritesInjury
2019
Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons
Park HA, Mnatsakanyan N, Broman K, Davis AU, May J, Licznerski P, Crowe-White KM, Lackey KH, Jonas EA. Alpha-Tocotrienol Prevents Oxidative Stress-Mediated Post-Translational Cleavage of Bcl-xL in Primary Hippocampal Neurons. International Journal Of Molecular Sciences 2019, 21: 220. PMID: 31905614, PMCID: PMC6982044, DOI: 10.3390/ijms21010220.Peer-Reviewed Original ResearchConceptsPrimary hippocampal neuronsHippocampal neuronsReactive oxygen speciesMitochondrial dysfunctionBcl-xLMitochondrial membrane potentialMitochondrial functionProduction of ROSExcitotoxic conditionsGlutamate challengeNeuroprotective propertiesMembrane potentialNeuronal deathExcitotoxic stimulationBcl-xL levelsNeuronal survivalIntracellular ATP depletionMitochondrial reactive oxygen speciesB cellsImportant causeDysfunctionNeuronsROS productionATP depletionNeurite outgrowthVEGF/VEGFR2 signaling regulates hippocampal axon branching during development
Luck R, Urban S, Karakatsani A, Harde E, Sambandan S, Nicholson L, Haverkamp S, Mann R, Martin-Villalba A, Schuman EM, Acker-Palmer A, de Almodóvar C. VEGF/VEGFR2 signaling regulates hippocampal axon branching during development. ELife 2019, 8: e49818. PMID: 31868583, PMCID: PMC6927742, DOI: 10.7554/elife.49818.Peer-Reviewed Original ResearchConceptsVEGF/VEGFR2Hippocampal axonsAxon branchingVEGF/VEGFR2 signalingHippocampal neurons resultsMouse hippocampal neuronsCA1 neuronsFunctional synapsesCA3 regionHippocampal neuronsNeurons resultsAngiogenic factorsHippocampus developmentAxonsReceptor VEGFR2NeuronsVEGFR2Neuronal networksVEGFNumber of filopodiaVEGFR2 signalingEphrinB2 regulates VEGFR2 during dendritogenesis and hippocampal circuitry development
Harde E, Nicholson L, Cuadrado B, Bissen D, Wigge S, Urban S, Segarra M, de Almodóvar C, Acker-Palmer A. EphrinB2 regulates VEGFR2 during dendritogenesis and hippocampal circuitry development. ELife 2019, 8: e49819. PMID: 31868584, PMCID: PMC6927743, DOI: 10.7554/elife.49819.Peer-Reviewed Original ResearchConceptsVascular endothelial growth factorLong-term potentiationDendritic arborizationCircuitry developmentSpine morphogenesisSpine head sizeEndothelial growth factorVEGFR2 internalizationCA3 synapsesCA3 regionDendritic arborsSpine maturationCompound miceHippocampal neuronsDendritic branchingNervous systemAngiogenic factorsEndothelial cellsGrowth factorNeuronsVEGFR2ArborizationMiceFunctional crosstalkEphrinB2TRPC5 regulates axonal outgrowth in developing retinal ganglion cells
Oda M, Yamamoto H, Matsumoto H, Ishizaki Y, Shibasaki K. TRPC5 regulates axonal outgrowth in developing retinal ganglion cells. Laboratory Investigation 2019, 100: 297-310. PMID: 31844148, DOI: 10.1038/s41374-019-0347-1.Peer-Reviewed Original ResearchConceptsRetinal ganglion cellsGanglion cell layerRetinal ganglion cell axon outgrowthTRPC5 expressionDepletion of intracellular calcium storesAmacrine cellsExcessive Ca<sup>2+</sup> entryDeath of retinal ganglion cellsExpression of TRPC5Ganglion cellsAxonal outgrowthIntracellular calcium storesMuller glial cellsNitric oxideMature retinal ganglion cellsRetinal cell typesIn situ hybridizationCentral nervous systemTRPC5 activityCalcium storesTRPC5Characteristic cell morphologyMouse retinaGlial cellsHippocampal neuronsVitamin E Prevents ΔN-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19)
Park H, Mnatsakanyan N, Broman K, Jonas E. Vitamin E Prevents ΔN-Bcl-xL-associate Mitochondrial Dysfunction in Primary Hippocampal Neurons (P14-024-19). Current Developments In Nutrition 2019, 3: nzz052.p14-024-19. PMCID: PMC6574370, DOI: 10.1093/cdn/nzz052.p14-024-19.Peer-Reviewed Original ResearchBcl-xL.Bcl-xLPrimary hippocampal neuronsMitochondrial dysfunctionRedox statusBcl-xL protein levelsCaspase-dependent cleavageAnti-apoptotic Bcl-xLMitochondrial redox statusPro-survival proteinsNeuronal deathMitochondrial oxidative stressHippocampal neuronsOxidative stressReactive oxygen species formationMitochondrial membraneCaspase activitySubsequent oxidative stressMitochondrial potentialMitochondrial functionNeuronal energy metabolismOxygen species formationDependent cleavageOxidative stress productionEnergy metabolismSystematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance
Smith LM, Kostylev MA, Lee S, Strittmatter SM. Systematic and standardized comparison of reported amyloid-β receptors for sufficiency, affinity, and Alzheimer's disease relevance. Journal Of Biological Chemistry 2019, 294: 6042-6053. PMID: 30787106, PMCID: PMC6463724, DOI: 10.1074/jbc.ra118.006252.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseAD brainLeukocyte immunoglobulin-like receptorsNogo receptor 1Human AD brainsImmunoglobulin-like receptorsB member 2Brains of individualsReceptor candidatesSoluble AβOsDisease relevanceCell surface expressionHippocampal neuronsMouse modelSynthetic AβAβO bindingMemory impairmentReceptor 1Cellular prion proteinNeuronal synapsesNgR1Molecular pathologyAβAβ speciesMember 2
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