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
Connectivity as a universal predictor of tau spreading in typical and atypical Alzheimer’s disease
de Bruin H, Groot C, ADNI, Barthel H, Bischof G, Boellaard R, Brendel M, Cash D, Coath W, Day G, Dickerson B, Doering E, Drzezga A, van Dyck C, van Eimeren T, van der Flier W, Fredericks C, Fryer T, van de Giessen E, Gordon B, Graff‐Radford J, Hobbs D, Höglinger G, Hönig M, Irwin D, Jones P, Josephs K, Katsumi Y, Lee E, Levin J, Malpetti M, McGinnis S, Mecca A, Nasrallah I, O'Brien J, O'Dell R, Palleis C, Perneczky R, Phillips J, Pijnenburg Y, Putcha D, Rahmouni N, Rosa‐Neto P, Rowe J, Rullmann M, Sabri O, Saur D, Schildan A, Schott J, Schroeter M, Servaes S, Sintini I, Stevenson J, Therriault J, Touroutoglou A, Trainer A, Visser D, Weston P, Whitwell J, Wolk D, Franzmeier N, Ossenkoppele R. Connectivity as a universal predictor of tau spreading in typical and atypical Alzheimer’s disease. Alzheimer's & Dementia 2024, 20: e085869. PMCID: PMC11714601, DOI: 10.1002/alz.085869.Peer-Reviewed Original ResearchAlzheimer's diseaseTau spreadingProgression of Alzheimer's diseaseTau-PETFunctional proximityPosterior patterningAD variantsTauPersonalized medicineTau-PET standardized uptake value ratiosVariantsWidespread patternAtypical ADDominant patternAtypical Alzheimer's diseaseRegionNeurodegenerationPositive probabilityPatternsConnectivity as a universal predictor of tau spreading in typical and atypical Alzheimer’s disease
de Bruin H, Groot C, ADNI, Barthel H, Bischof G, Boellaard R, Brendel M, Cash D, Coath W, Day G, Dickerson B, Doering E, Drzezga A, van Dyck C, van Eimeren T, van der Flier W, Fredericks C, Fryer T, van de Giessen E, Gordon B, Graff‐Radford J, Hobbs D, Höglinger G, Hönig M, Irwin D, Jones P, Josephs K, Katsumi Y, Lee E, Levin J, Malpetti M, McGinnis S, Mecca A, Nasrallah I, O'Brien J, O'Dell R, Palleis C, Perneczky R, Phillips J, Pijnenburg Y, Putcha D, Rahmouni N, Rosa‐Neto P, Rowe J, Rullmann M, Sabri O, Saur D, Schildan A, Schott J, Schroeter M, Servaes S, Sintini I, Stevenson J, Therriault J, Touroutoglou A, Trainer A, Visser D, Weston P, Whitwell J, Wolk D, Franzmeier N, Ossenkoppele R. Connectivity as a universal predictor of tau spreading in typical and atypical Alzheimer’s disease. Alzheimer's & Dementia 2024, 20: e093663. PMCID: PMC11713789, DOI: 10.1002/alz.093663.Peer-Reviewed Original ResearchAlzheimer's diseaseTau spreadingProgression of Alzheimer's diseaseTau-PETFunctional proximityPosterior patterningAD variantsTauPersonalized medicineTau-PET standardized uptake value ratiosVariantsWidespread patternAtypical ADDominant patternAtypical Alzheimer's diseaseRegionNeurodegenerationPatternsAPOE 4‐related blood–brain barrier breakdown is associated with microstructural abnormalities
Reas E, Solders S, Tsiknia A, Triebswetter C, Shen Q, Rivera C, Andrews M, Alderson‐Myers A, Brewer J. APOE 4‐related blood–brain barrier breakdown is associated with microstructural abnormalities. Alzheimer's & Dementia 2024, 20: 8615-8624. PMID: 39411970, PMCID: PMC11667544, DOI: 10.1002/alz.14302.Peer-Reviewed Original ResearchAPOE4 carriersAlzheimer's diseaseAmyloid-negative individualsAmyloid-betaAmyloid-positive individualsApoE4AD cascadeAmyloidBlood-brain barrierAPOE 4Magnetic resonance imagingBrain microstructureAbsence of cognitive declinePreclinical ADLinear regression assessed associationsAmyloid positivityNeurodegenerative changesCortical gray matterCognitive declineMicrostructural abnormalitiesAssociated with microstructural abnormalitiesCognitive statusApoNeurodegenerationOlder adultsCellular Prion Protein Conformational Shift after Liquid–Liquid Phase Separation Regulated by a Polymeric Antagonist and Mutations
Liu Y, Tuttle M, Kostylev M, Roseman G, Zilm K, Strittmatter S. Cellular Prion Protein Conformational Shift after Liquid–Liquid Phase Separation Regulated by a Polymeric Antagonist and Mutations. Journal Of The American Chemical Society 2024, 146: 27903-27914. PMID: 39326869, PMCID: PMC11469297, DOI: 10.1021/jacs.4c10590.Peer-Reviewed Original ResearchConceptsLiquid-liquid phase separationCellular prion proteinAssociated with neurodegenerative diseasesAmyloid-bMaturation processDisordered proteinsPrion proteinConformational shiftProtein conformationConformational changesNeurodegenerative diseasesInduction conditionsConformational statesProteinPrPMutationsPhase separationSaturating concentrationsMolecular motionSolid-like stateMaturationDisease-related cognitive deficitsNeurodegenerationInductionAlzheimerDiffusion MRI Allows Capturing the Amyloid-β and τ Proteins Status in Alzheimer’s Disease Continuum
Dolci G, Cruciani F, Brusini L, Pini L, Galazzo I, Calhoun V, Menegaz G. Diffusion MRI Allows Capturing the Amyloid-β and τ Proteins Status in Alzheimer’s Disease Continuum. 2024, 00: 1-5. DOI: 10.1109/isbi56570.2024.10635105.Peer-Reviewed Original ResearchGonadal hormone deprivation regulates response to tibolone in neurodegenerative pathways
McGovern A, Arevalo M, Ciordia S, Garcia-Segura L, Barreto G. Gonadal hormone deprivation regulates response to tibolone in neurodegenerative pathways. The Journal Of Steroid Biochemistry And Molecular Biology 2024, 241: 106520. PMID: 38614433, DOI: 10.1016/j.jsbmb.2024.106520.Peer-Reviewed Original ResearchHormone therapyEfficacy of hormone therapyEffects of hormone therapyPathways of neurodegenerationBilateral oophorectomyHormone deprivationAndrogen pathwayIncreased risk of neurodegenerationTherapeutic efficacyTiboloneOxidative phosphorylationIncreased riskProteomic analysisCalcium signalingCellular respirationHormonal declineNeurodegenerative pathwaysDrug typeRisk of neurodegenerationInterconnected pathwaysPathwayNeurodegenerationSexImmunological aspects of central neurodegeneration
Niso-Santano M, Fuentes J, Galluzzi L. Immunological aspects of central neurodegeneration. Cell Discovery 2024, 10: 41. PMID: 38594240, PMCID: PMC11004155, DOI: 10.1038/s41421-024-00666-z.Peer-Reviewed Original ResearchCentral neurodegenerationImmune effector cellsTarget immune cellsHuntington's diseaseNeuronal defectsCentral nervous systemEffector cellsImmunological dysfunctionAlzheimer's diseaseNeurodegenerative disordersImmune cellsImmunological mechanismsImmunological aspectsTherapeutic strategiesClinically relevant neuroprotective effectsNeuronal populationsNeurodegenerative conditionsNervous systemNeuroprotective effectsDiseaseNeurodegenerative syndromeTherapeutic purposesNeurodegenerationParkinson's diseaseCells
2023
A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels
Dutta D, Kanca O, Byeon S, Marcogliese P, Zuo Z, Shridharan R, Park J, Lin G, Ge M, Heimer G, Kohler J, Wheeler M, Kaipparettu B, Pandey A, Bellen H. A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels. Nature Metabolism 2023, 5: 1595-1614. PMID: 37653044, PMCID: PMC11151872, DOI: 10.1038/s42255-023-00873-0.Peer-Reviewed Original ResearchConceptsFatty acid synthesisFe-S cluster biogenesisMitochondrial fatty acid synthesisCeramide levelsMost eukaryotic cellsElevated ceramide levelsIron metabolismCluster biogenesisEukaryotic cellsLoss of functionCellular lipidomeEnoyl coenzymeNeurodegenerative phenotypeIron homeostasisHuman-derived fibroblastsMechanistic linkAcid synthesisCeramideMECRMetabolismNeurodegenerationMtFASBiogenesisLast stepMitochondriaTumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington’s disease
Mansky R, Greguske E, Yu D, Zarate N, Intihar T, Tsai W, Brown T, Thayer M, Kumar K, Gomez-Pastor R. Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington’s disease. Cell Reports 2023, 42: 112198. PMID: 36867535, PMCID: PMC10128052, DOI: 10.1016/j.celrep.2023.112198.Peer-Reviewed Original ResearchConceptsMajor transcription factorTumor suppressor p53Huntington's diseaseHtt aggregationTranscription factorsE3 ligase MDM2Protein degradationSuppressor p53Reciprocal regulationMutant HttP53 stabilizationMolecular differencesCell proliferationHSF1Neurodegenerative diseasesP53Most cancersNeurodegenerationP53 deletionTranscriptionDegradationDeletionAbundanceHTT
2022
Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death
Aber ER, Griffey CJ, Davies T, Li AM, Yang YJ, Croce KR, Goldman JE, Grutzendler J, Canman JC, Yamamoto A. Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death. Cell Reports 2022, 41: 111480. PMID: 36261002, PMCID: PMC9639605, DOI: 10.1016/j.celrep.2022.111480.Peer-Reviewed Original ResearchConceptsCell typesLive-cell imagingNeurodegenerative disease pathophysiologySuch cell typesMouse geneticsAdult-onset neurodegenerative diseaseMacroautophagyCell imagingNeurodegenerative diseasesMyelin proteinsNeurodegenerationDisease pathophysiologyTurnoverMature oligodendrocytesCentral nervous systemAmphisomesMyelin sheath structureNeural functionNervous systemMyelin turnoverGeneticsMyelin sheathProgressive motor declineProteinHomeostasisAn unexpected protein aggregate in diseased and ageing brains
Takahashi H, Strittmatter SM. An unexpected protein aggregate in diseased and ageing brains. Nature 2022, 605: 227-228. PMID: 35379977, DOI: 10.1038/d41586-022-00873-2.Peer-Reviewed Original ResearchConnectomic-genetic signatures in the cerebral small vessel disease
Gutiérrez-Zúñiga R, Diez I, Bueichekú E, Kim C, Orwig W, Montal V, Fuentes B, Díez-Tejedor E, Fernández M, Sepulcre J. Connectomic-genetic signatures in the cerebral small vessel disease. Neurobiology Of Disease 2022, 167: 105671. PMID: 35231560, PMCID: PMC8957615, DOI: 10.1016/j.nbd.2022.105671.Peer-Reviewed Original ResearchRedesigning therapies for pantothenate kinase–associated neurodegeneration
Munshi MI, Yao SJ, Mamoun C. Redesigning therapies for pantothenate kinase–associated neurodegeneration. Journal Of Biological Chemistry 2022, 298: 101577. PMID: 35041826, PMCID: PMC8861153, DOI: 10.1016/j.jbc.2022.101577.Peer-Reviewed Original ResearchConceptsPantothenate kinase-associated neurodegenerationCellular metabolic processesMore common diseasesMetabolic processesPhysiological importancePANK2 genePantothenate kinaseCoenzyme ACoenzyme A.Rare genetic disorderCommon neurodegenerative diseaseNeurodegenerative diseasesGenetic disordersNeurodegenerationNew avenuesBiosynthesisKinaseGenesNew lightFuture investigationsCofactorMutationsCommon diseaseEnzymeAlzheimer's disease
2021
Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers
Robb W, Khan O, Ahmed H, Li J, Moore E, Cambronero F, Pechman K, Liu D, Gifford K, Landman B, Donahue M, Hohman T, Jefferson A. Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers. Cerebrovascular And Brain Metabolism Reviews 2021, 42: 642-655. PMID: 34743630, PMCID: PMC9051148, DOI: 10.1177/0271678x211056393.Peer-Reviewed Original ResearchConceptsEpisodic memory performanceCognitive performancePathogenesis of Alzheimer's diseaseMemory performanceAlzheimer's disease-related neurodegenerationPoorer cognitive performanceE4 carriersLateral ventricle volumeExecutive functionEpisodic memoryOxygen homeostasisDisease-related neurodegenerationAlzheimer's diseaseBrain agingCognitive impairmentNeuroimaging variablesE4 statusCerebral metabolic rateVentricle volumeOlder adultsBad languageHippocampalNeurodegenerationMetabolic rateMetabolismTau‐Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease
Das S, Lyu X, Duong M, Xie L, McCollum L, Flores R, DiCalogero M, Irwin D, Dickerson B, Nasrallah I, Yushkevich P, Wolk D, Weiner M, Aisen P, Petersen R, Jack C, Jagust W, Trojanowki J, Toga A, Beckett L, Green R, Saykin A, Morris J, Shaw L, Liu E, Montine T, Thomas R, Donohue M, Walter S, Gessert D, Sather T, Jiminez G, Harvey D, Donohue M, Bernstein M, Fox N, Thompson P, Schuff N, DeCArli C, Borowski B, Gunter J, Senjem M, Vemuri P, Jones D, Kantarci K, Ward C, Koeppe R, Foster N, Reiman E, Chen K, Mathis C, Landau S, Cairns N, Householder E, Reinwald L, Lee V, Korecka M, Figurski M, Crawford K, Neu S, Foroud T, Potkin S, Shen L, Kelley F, Kim S, Nho K, Kachaturian Z, Frank R, Snyder P, Molchan S, Kaye J, Quinn J, Lind B, Carter R, Dolen S, Schneider L, Pawluczyk S, Beccera M, Teodoro L, Spann B, Brewer J, Vanderswag H, Fleisher A, Heidebrink J, Lord J, Petersen R, Mason S, Albers C, Knopman D, Johnson K, Doody R, Meyer J, Chowdhury M, Rountree S, Dang M, Stern Y, Honig L, Bell K, Ances B, Morris J, Carroll M, Leon S, Householder E, Mintun M, Schneider S, Oliver A, Marson D, Griffith R, Clark D, Geld‐Macher D, Brockington J, Roberson E, Grossman H, Mitsis E, Toledo‐Morrell L, Shah R, Duara R, Varon D, Greig M, Roberts P, Albert M, Onyike C, D'Agostino D, Kielb S, Galvin J, Pogorelec D, Cerbone B, Michel C, Rusinek H, Leon M, Glodzik L, De Santi S, Doraiswamy P, Petrella J, Wong T, Arnold S, Karlawish J, Wolk D, Smith C, Jicha G, Hardy P, Sinha P, Oates E, Conrad G, Lopez O, Oakley M, Simpson D, Porsteinsson A, Goldstein B, Martin K, Makino K, Ismail M, Brand C, Mulnard R, Thai G, Ortiz C, Womack K, Mathers D, Quiceno M, Arrastia R, King R, Weiner M, Martin Cook K, DeVous M, Levey A, Lah J, Cellar J, Bums J, Anderson H, Swerdlow R, Apostolova L, Tingus K, Woo E, Silverman D, Lu P, Bartzokis G, Graff Radford N, Parfitt F, Kendall T, Johnson H, Farlow M, Hake A, Matthews B, Herring S, Hunt C, Dyck C, Carson R, MacAvoy M, Chertkow H, Bergman H, Hosein C, Black S, Stefanovic B, Caldwell C, Hsiung G, Feldman H, Mudge B, Assaly M, Kertesz A, Rogers J, Trost D, Bernick C, Munic D, Kerwin D, Mesulam M, Lipowski K, Wu C, Johnson N, Sadowsky C, Martinez W, Villena T, Turner R, Kathleen Johnson N, Brigid Reynolds N, Sperling R, Johnson K, Marshall G, Frey M, Yesavage J, Taylor J, Lane B, Rosen A, Tinklenberg J, Sabbagh M, Belden C, Jacobson S, Sirrel S, Kowall N, Killiany R, Budson A, Norbash A, Johnson P, Obisesan T, Wolday S, Allard J, Lerner A, Ogrocki P, Hudson L, Fletcher E, Carmichael O, Olichney J, DeCarli C, Kittur S, Borrie M, Lee T, Bartha R, Johnson S, Asthana S, Carlsson C, Potkin S, Preda A, Nguyen D, Tariot P, Fleisher A, Reeder S, Bates V, Capote H, Rainka M, Scharre D, Kataki M, Adeli A, Zimmerman E, Celmins D, Brown A, Pearlson G, Blank K, Anderson K, Santulli R, Kitzmiller T, Schwartz E, Sink K, Williamson J, Garg P, Watkins F, Ott B, Querfurth H, Tremont G, Salloway S, Malloy P, Correia S, Rosen H, Miller B, Mintzer J, Spicer K, Bachman D, Finger E, Pasternak S, Rachinsky I, Rogers J, Kertesz A, Drost D, Pomara N, Hernando R, Sarrael A, Schultz S, Boles Ponto L, Shim H, Smith K, Relkin N, Chaing G, Raudin L, Smith A, Fargher K, Raj B. Tau‐Atrophy Variability Reveals Phenotypic Heterogeneity in Alzheimer's Disease. Annals Of Neurology 2021, 90: 751-762. PMID: 34617306, PMCID: PMC8841129, DOI: 10.1002/ana.26233.Peer-Reviewed Original ResearchConceptsData-driven subgroupsAlzheimer's diseaseLow atrophyCortical thicknessBrain regionsWhite matter hyperintensity lesionsModulatory factorsAmyloid-positive individualsSubsequent cognitive impairmentLevels of tauGray matter regionsAnn NeurolDownstream neurodegenerationHyperintensity lesionsTau neurofibrillaryTau burdenClinical trialsCognitive impairmentMatter regionsDiseaseMultiple underlying factorsNeurodegenerationAtrophyCohortSUVRAge-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity
Miazek A, Zalas M, Skrzymowska J, Bogin BA, Grzymajło K, Goszczynski TM, Levine ZA, Morrow JS, Stankewich MC. Age-dependent ataxia and neurodegeneration caused by an αII spectrin mutation with impaired regulation of its calpain sensitivity. Scientific Reports 2021, 11: 7312. PMID: 33790315, PMCID: PMC8012654, DOI: 10.1038/s41598-021-86470-1.Peer-Reviewed Original ResearchConceptsSpectrin cleavageCalpain cleavage sitesCalcium-activated proteaseGlobal neurodegenerationTraumatic encephalopathyC57BL/6J miceDendritic integrityExcessive activationNeuronal integrityProgressive ataxiaImpaired regulationCalpain activationCalpain sensitivityPhysiologic significanceNeurodegenerative diseasesNeuronal developmentCalpain proteolysisCalpain proteasesCalcium-dependent bindingAtaxiaNeurodegenerationCalpainActivated calpainSubstrate-level regulationCaM affinityPower Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models
Woo J, Cho H, Seol Y, Kim SH, Park C, Yousefian-Jazi A, Hyeon SJ, Lee J, Ryu H. Power Failure of Mitochondria and Oxidative Stress in Neurodegeneration and Its Computational Models. Antioxidants 2021, 10: 229. PMID: 33546471, PMCID: PMC7913624, DOI: 10.3390/antiox10020229.Peer-Reviewed Original ResearchOxidative stressMitochondrial functionMitochondrial dysfunctionAntioxidant therapeutic strategiesAmyotrophic lateral sclerosisNeuronal damageLateral sclerosisParkinson's diseaseTherapeutic strategiesNeuronal activitySubcellular eventsAlzheimer's diseaseBiochemical energyNeurodegenerative disordersLiving organismDiseaseHuntington's diseaseNeurodegenerationArt computational modelsMitochondriaDysfunctionBrainSclerosisStressOrganisms
2020
Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation
Kelmer Sacramento E, Kirkpatrick J, Mazzetto M, Baumgart M, Bartolome A, Di Sanzo S, Caterino C, Sanguanini M, Papaevgeniou N, Lefaki M, Childs D, Bagnoli S, Terzibasi Tozzini E, Di Fraia D, Romanov N, Sudmant P, Huber W, Chondrogianni N, Vendruscolo M, Cellerino A, Ori A. Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation. Molecular Systems Biology 2020, 16: msb209596. PMID: 32558274, PMCID: PMC7301280, DOI: 10.15252/msb.20209596.Peer-Reviewed Original ResearchConceptsProtein homeostasisProteasome activityPost-transcriptional mechanismsAge-regulating proteinDriver of neurodegenerationProteome dynamicsProtein complexesTranscriptomic dataProtein aggregatesAge-related neurodegenerationProteomic signatureAssembly/Loss of stoichiometryProteasome levelsEarly eventsProteinHomeostasisProgressive lossNeurodegenerationCausative eventAging processTranscriptomicsNothobranchiusBrain agingRibosomesNovel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome
Brodsky NN, Boyarchuk O, Kovalchuk T, Hariyan T, Rice A, Ji W, Khokha M, Lakhani S, Lucas CL. Novel compound heterozygous variants in NHLRC2 in a patient with FINCA syndrome. Journal Of Human Genetics 2020, 65: 911-915. PMID: 32435055, DOI: 10.1038/s10038-020-0776-0.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAngiomatosisBrain NeoplasmsCardiomegalyChild, PreschoolExome SequencingFibrosisHeterozygoteHumansIntracellular Signaling Peptides and ProteinsLung DiseasesMaleModels, MolecularNeurodegenerative DiseasesPedigreePoint MutationProtein ConformationProtein DomainsSequence AlignmentSequence Homology, Amino AcidSyndromeConceptsWhole-exome sequencingNovel compound heterozygous variantsCompound heterozygous variantsUkrainian patientsClinical featuresNovel variantsNew patientsHealthy humansCompound heterozygous combinationPatientsHeterozygous variantsSyndromeFinnish childrenNHLRC2Sanger sequencingFibrosisDiseaseGnomAD databaseN-terminal thioredoxinCentral regulatorVariantsNeurodegeneration
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