2024
A framework for translating tauopathy therapeutics: Drug discovery to clinical trials
Feldman H, Cummings J, Boxer A, Staffaroni A, Knopman D, Rizzo S, Territo P, Arnold S, Ballard C, Beher D, Boeve B, Dacks P, Diaz K, Ewen C, Fiske B, Gonzalez M, Harris G, Hoffman B, Martinez T, McDade E, Nisenbaum L, Palma J, Quintana M, Rabinovici G, Rohrer J, Rosen H, Troyer M, Kim D, Tanzi R, Zetterberg H, Ziogas N, May P, Rommel A. A framework for translating tauopathy therapeutics: Drug discovery to clinical trials. Alzheimer's & Dementia 2024, 20: 8129-8152. PMID: 39316411, PMCID: PMC11567863, DOI: 10.1002/alz.14250.Peer-Reviewed Original ResearchPrimary tauopathiesClinically heterogeneous neurodegenerative diseasesTau protein aggregationHeterogeneous neurodegenerative diseaseSurrogate disease biomarkersTauopathiesProtein aggregationDefinition of rare diseasesAlzheimer's diseaseNeurodegenerative diseasesClinical trialsEarly-phase clinical trialsEarly-phase trialsDisease biomarkersFrontotemporal degenerationDrug developmentProgressive supranuclear palsyDiscovery to clinical trialsSelection of targetsTherapeuticsPharmacodynamic biomarkersCharacterizing the Effects of Progranulin Reduction on Tau Pathology and Phenotypes in a Mouse Model of Tauopathy (P4-9.016)
Bhagwagar S, Takahashi H, Strittmatter S. Characterizing the Effects of Progranulin Reduction on Tau Pathology and Phenotypes in a Mouse Model of Tauopathy (P4-9.016). Neurology 2024, 102 DOI: 10.1212/wnl.0000000000205227.Peer-Reviewed Original ResearchHead-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases
Aguero C, Dhaynaut M, Amaral A, Moon S, Neelamegam R, Scapellato M, Carazo-Casas C, Kumar S, El Fakhri G, Johnson K, Frosch M, Normandin M, Gómez-Isla T. Head-to-head comparison of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 postmortem binding across the spectrum of neurodegenerative diseases. Acta Neuropathologica 2024, 147: 25. PMID: 38280071, PMCID: PMC10822013, DOI: 10.1007/s00401-023-02672-z.Peer-Reviewed Original ResearchConceptsNon-AD tauopathiesTau aggregationTau PET tracersDNA-binding proteinsBinds to neurofibrillary tanglesSecond-generation tau tracersTransactive response DNA-binding proteinSpectrum of neurodegenerative diseasesNeurofibrillary tanglesTau lesionsMelanin-containing cellsTDP-43Binding signalTauopathiesBinding targetsCerebral amyloid angiopathyOff-target bindingB-amyloidBinding patternsNeurodegenerative diseasesTau tracersTauBinding to areasBinding profilesBinding
2023
Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality
Hu Z, Chen P, Li W, Douglas T, Hines J, Liu Y, Crews C. Targeted Dephosphorylation of Tau by Phosphorylation Targeting Chimeras (PhosTACs) as a Therapeutic Modality. Journal Of The American Chemical Society 2023, 145: 4045-4055. PMID: 36753634, PMCID: PMC11670127, DOI: 10.1021/jacs.2c11706.Peer-Reviewed Original ResearchProtein tauTau dephosphorylationDisease-modifying therapiesMicrotubule-associated protein tauTau phosphorylation levelsImportant pathological roleTherapeutic modalitiesTau phosphorylationAlzheimer's diseaseTau proteinTherapeutic potentialPathological roleKinase inhibitorsEnhanced downregulationLimited benefitPhosphorylation levelsTauTauopathiesDiseaseCurrent strategiesTau phosphatase
2022
The lateral entorhinal cortex is a hub for local and global dysfunction in early Alzheimer’s disease states
Mandino F, Yeow LY, Bi R, Sejin L, Bae HG, Baek SH, Lee CY, Mohammad H, Horien C, Teoh CL, Lee JH, Lai MK, Jung S, Fu Y, Olivo M, Gigg J, Grandjean J. The lateral entorhinal cortex is a hub for local and global dysfunction in early Alzheimer’s disease states. Cerebrovascular And Brain Metabolism Reviews 2022, 42: 1616-1631. PMID: 35466772, PMCID: PMC9441719, DOI: 10.1177/0271678x221082016.Peer-Reviewed Original ResearchConceptsAlzheimer's diseaseEntorhinal cortexFunctional connectivity lossEarly AD stagesEarly Alzheimer's diseaseLateral entorhinal cortexVentral networkSynaptic hyperexcitabilityAD progressionGlobal dysfunctionMouse modelOptogenetic activationProjection targetsPathophysiological modelAD stagesMice showNetwork alterationsActive phenotypeNeuronal facilitationEarly hallmarkDiseaseActivity alterationsFMRI signalsNeuronal underpinningsTauopathies
2021
Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET
Song M, Beyer L, Kaiser L, Barthel H, van Eimeren T, Marek K, Nitschmann A, Scheifele M, Palleis C, Respondek G, Kern M, Biechele G, Hammes J, Bischof G, Barbe M, Onur Ö, Jessen F, Saur D, Schroeter M, Rumpf J, Rullmann M, Schildan A, Patt M, Neumaier B, Barret O, Madonia J, Russell D, Stephens A, Mueller A, Roeber S, Herms J, Bötzel K, Danek A, Levin J, Classen J, Höglinger G, Bartenstein P, Villemagne V, Drzezga A, Seibyl J, Sabri O, Boening G, Ziegler S, Brendel M. Binding characteristics of [18F]PI-2620 distinguish the clinically predicted tau isoform in different tauopathies by PET. Cerebrovascular And Brain Metabolism Reviews 2021, 41: 2957-2972. PMID: 34044665, PMCID: PMC8545042, DOI: 10.1177/0271678x211018904.Peer-Reviewed Original Research
2020
Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy
Tang SJ, Fesharaki-Zadeh A, Takahashi H, Nies SH, Smith LM, Luo A, Chyung A, Chiasseu M, Strittmatter SM. Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy. Acta Neuropathologica Communications 2020, 8: 96. PMID: 32611392, PMCID: PMC7329553, DOI: 10.1186/s40478-020-00976-9.Peer-Reviewed Original ResearchConceptsRepetitive closed head injuriesMemory deficitsPhospho-tau accumulationChronic variable stressPersistent memory deficitsP301S transgenic miceClosed head injuryFyn inhibitionPassive avoidance learningFyn kinaseGlial activationPhospho-tauPresynaptic markersSynapse lossTau accumulationHead injurySynapse densityPhosphorylated tauTherapeutic benefitTransgenic miceBehavioral improvementTrauma modelTauopathiesSpatial memoryAvoidance learning
2019
O5‐04‐05: A NEW THERAPEUTIC STRATEGY FOR TAUOPATHIES: DISCOVERY OF HIGHLY POTENT BRAIN PENETRANT PROTACTM DEGRADER MOLECULES THAT TARGET PATHOLOGIC TAU PROTEIN SPECIES
Cacace A, Chandler J, Flanagan J, Berlin M, Cadelina G, Pizzano J, Bookbinder M, Crews C, Crew A, Taylor I, Houston J. O5‐04‐05: A NEW THERAPEUTIC STRATEGY FOR TAUOPATHIES: DISCOVERY OF HIGHLY POTENT BRAIN PENETRANT PROTACTM DEGRADER MOLECULES THAT TARGET PATHOLOGIC TAU PROTEIN SPECIES. Alzheimer's & Dementia 2019, 15: p1624-p1624. DOI: 10.1016/j.jalz.2019.06.4856.Peer-Reviewed Original ResearchP4‐576: CONCORDANCE BETWEEN 18F‐PI‐2620 TAU PET/MRI IMAGING AND CLINICAL OUTCOMES IN ALZHEIMER DISEASE AND OTHER TAUOPATHIES
Koran M, Davidzon G, Azevedo C, Toueg T, Nadiadwala A, Castillo J, Hall J, Sha S, Fredericks C, Greicius M, Wagner A, Zaharchuk G, Chin F, Mormino E. P4‐576: CONCORDANCE BETWEEN 18F‐PI‐2620 TAU PET/MRI IMAGING AND CLINICAL OUTCOMES IN ALZHEIMER DISEASE AND OTHER TAUOPATHIES. Alzheimer's & Dementia 2019, 15: p1541-p1541. DOI: 10.1016/j.jalz.2019.08.124.Peer-Reviewed Original Research
2017
[IC‐P‐192]: PRECLINICAL CHARACTERIZATION OF PI‐2620, A NOVEL TAU PET TRACER FOR DETECTION OF TAU IN AD AND OTHER TAUOPATHIES
Mueller A, Kroth H, Schieferstein H, Berndt M, Oden F, Capotosti F, Molette J, Juergens T, Darmency V, Schmitt‐Willich H, Hickman D, Tamagnan G, Pfeifer A, Dinkelborg L, Muhs A, Stephens A. [IC‐P‐192]: PRECLINICAL CHARACTERIZATION OF PI‐2620, A NOVEL TAU PET TRACER FOR DETECTION OF TAU IN AD AND OTHER TAUOPATHIES. Alzheimer's & Dementia 2017, 13: p141-p142. DOI: 10.1016/j.jalz.2017.06.2567.Peer-Reviewed Original Research[P2–381]: PRECLINICAL CHARACTERIZATION OF PI‐2620, A NOVEL TAU PET TRACER FOR DETECTION OF TAU IN AD AND OTHER TAUOPATHIES
Mueller A, Kroth H, Schieferstein H, Berndt M, Oden F, Capotosti F, Molette J, Juergens T, Darmency V, Schmitt‐Willich H, Hickman D, Tamagnan G, Pfeifer A, Dinkelborg L, Muhs A, Stephens A. [P2–381]: PRECLINICAL CHARACTERIZATION OF PI‐2620, A NOVEL TAU PET TRACER FOR DETECTION OF TAU IN AD AND OTHER TAUOPATHIES. Alzheimer's & Dementia 2017, 13: p774-p774. DOI: 10.1016/j.jalz.2017.06.1036.Peer-Reviewed Original ResearchPathological correlations of [F‐18]‐AV‐1451 imaging in non‐alzheimer tauopathies
Marquié M, Normandin M, Meltzer A, Chong M, Andrea N, Antón‐Fernández A, Klunk W, Mathis C, Ikonomovic M, Debnath M, Bien E, Vanderburg C, Costantino I, Makaretz S, DeVos S, Oakley D, Gomperts S, Growdon J, Domoto‐Reilly K, Lucente D, Dickerson B, Frosch M, Hyman B, Johnson K, Gómez‐Isla T. Pathological correlations of [F‐18]‐AV‐1451 imaging in non‐alzheimer tauopathies. Annals Of Neurology 2017, 81: 117-128. PMID: 27997036, PMCID: PMC5319193, DOI: 10.1002/ana.24844.Peer-Reviewed Original ResearchConceptsNon-Alzheimer tauopathiesTau lesionsDetection of tau aggregatesBinding to tau lesionsTau measuresPositron emission tomographyMutation carriersTau filamentsProgressive supranuclear palsyTau aggregationPostmortem brain samplesAlzheimer brainsTauopathiesAV-1451Atypical tauopathyBrain regionsOff-target bindingBinding patternsBinding assaysBasal gangliaEntorhinal cortexSubstantia nigraTauMAPT
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