ArticleMolecular therapy : the journal of the American Society of Gene Therapy2024
A small TAT-TrkB peptide prevents BDNF receptor cleavage and restores synaptic physiology in Alzheimer's disease.
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Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 11 papers.
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11citing papers in PubMed
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11 citing papers in PubMed.
- Targeting the FOXO4-p53 axis by retro-inverso peptide senolytic agents: a pharmacological strategy to mitigate brain aging and cognitive decline.Naunyn-Schmiedeberg's archives of pharmacology · 2026Review
- From gastric to neuroprotection: pantoprazole mitigates epilepsy via TrkB/BDNF and KCC2 modulation.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- ROS-responsive transmembrane peptide-antibody conjugate eyedrops for the non-invasive treatment of choroidoretinopathy.Materials today. Bio · 2026Article
- Disruption of BDNF signalling in neuropathologies.Biochemical Society transactions · 2026Review
- BDNF-amyloid-Frontiers in molecular neuroscience · 2026Review
- Sigma-1-targeting multimodal compound HBK-15 reverses memory deficits and restores hippocampal plasticity under NMDA hypofunction.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2026Article
- The Intricate Relationship of Trk Receptors in Brain Diseases and Disorders.Molecular neurobiology · 2025Review
- Hippocampal Neurogenesis in Alzheimer's Disease: Multimodal Therapeutics and the Neurogenic Impairment Index Framework.International journal of molecular sciences · 2025Review
- Targeting the RAGE-RIPK1 binding site attenuates diabetes-associated cognitive deficits.Journal of neuroinflammation · 2025Article
- Cleavage of the TrkB-FL receptor during epileptogenesis: insights from a kainic acid-induced model of epilepsy and human samples.Pharmacological research · 2025Article
- Exercise modulation of BDNF/TrkB signaling in Parkinson's disease: an evidence-calibrated review of neuroprotective mechanisms, biomarker limitations, and translational gaps.Frontiers in neurologyReview
Corrections and comments
- Erratum issued
Authors and funding
44 authors.
João Fonseca-GomesInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Tiago Costa-CoelhoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Mafalda Ferreira-MansoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Sara Inteiro-OliveiraInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Sandra H VazInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Nuno Alemãn-SerranoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Henrique Atalaia-BarbacenaInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Leonor Ribeiro-RodriguesInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Rita M RamalhoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Rui PintoLaboratory of Systems Integration Pharmacology, Clinical, and Regulatory Science, Research Institute for Medicines (iMED.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal; Dr. Joaquim Chaves Laboratório de Análises Clínicas, 2790-224 Carnaxide, Portugal.
Hugo Vicente MirandaiNOVA4Health, NOVA Medical School, NMS, Universidade NOVA de Lisboa, 1169-056 Lisbon, Portugal.
Sara R TanqueiroInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Carolina de Almeida-BorlidoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Maria João RamalhoLEPABE - Laboratory for Process Engineering, Environment, Biotechnology, and Energy, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal; ALiCE-Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal.
Catarina Miranda-LourençoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Rita F BeloInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Catarina B FerreiraInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Vera NevesInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Diogo M RomboInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Ricardo ViaisInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Juzoh UmemoriGene and Cell Technology, A.I. Virtanen Institute, University of Eastern Finland, Neulaniementie 2, 70211 Kuopio, Finland.
Ivo C MartinsInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
André Jerónimo-SantosInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
António CaetanoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Nuno MansoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Petra MäkinenInstitute of Biomedicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Mikael MarttinenInstitute of Biomedicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland; Structural and Computational Biology, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
Mari TakaloInstitute of Biomedicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Michael BremangProteome Sciences, Coveham House, Downside Bridge Road, KT11 3EP Cobham, UK.
Ian PikeProteome Sciences, Coveham House, Downside Bridge Road, KT11 3EP Cobham, UK.
Annakaisa HaapasaloA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
Joana A LoureiroLEPABE - Laboratory for Process Engineering, Environment, Biotechnology, and Energy, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal; ALiCE-Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal.
Maria Carmo PereiraLEPABE - Laboratory for Process Engineering, Environment, Biotechnology, and Energy, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal; ALiCE-Associate Laboratory in Chemical Engineering, Faculty of Engineering, University of Porto, 4200-465 Porto, Portugal.
Nuno C SantosInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Tiago F OuteiroDepartment of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37073 Göttingen, Germany; Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany; Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK; German Center for Neurodegenerative Diseases (DZNE), 37075 Göttingen, Germany.
Miguel A R B CastanhoInstituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Adelaide FernandesResearch Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal; Department of Pharmaceutical Sciences and Medicines, Faculdade de Farmácia, Universidade de Lisboa, 1649-003 Lisbon, Portugal.
Mikko HiltunenInstitute of Biomedicine, School of Medicine, University of Eastern Finland, P.O. Box 1627, 70211 Kuopio, Finland.
Carlos B DuarteCNC - Center for Neuroscience and Cell Biology and Department of Life Sciences, University of Coimbra, 3004-504 Coimbra, Portugal.
Eero CastrénNeuroscience Center, University of Helsinki, 00014 Helsinki, Finland.
Alexandre de MendonçaInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Ana M SebastiãoInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Tiago M RodriguesInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal. Electronic address: tiago.rodrigues@iob.ch.
Maria José DiógenesInstituto de Farmacologia e Neurociências, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal. Electronic address: diogenes@medicina.ulisboa.pt.
Funding
No grant is acknowledged in the PubMed record.
Abstract
In Alzheimer's disease (AD), amyloid β (Aβ)-triggered cleavage of TrkB-FL impairs brain-derived neurotrophic factor (BDNF) signaling, thereby compromising neuronal survival, differentiation, and synaptic transmission and plasticity. Using cerebrospinal fluid and postmortem human brain samples, we show that TrkB-FL cleavage occurs from the early stages of the disease and increases as a function of pathology severity. To explore the therapeutic potential of this disease mechanism, we designed small TAT-fused peptides and screened their ability to prevent TrkB-FL receptor cleavage. Among these, a TAT-TrkB peptide with a lysine-lysine linker prevented TrkB-FL cleavage both in vitro and in vivo and rescued synaptic deficits induced by oligomeric Aβ in hippocampal slices. Furthermore, this TAT-TrkB peptide improved the cognitive performance, ameliorated synaptic plasticity deficits and prevented Tau pathology progression in vivo in the 5XFAD mouse model of AD. No evidence of liver or kidney toxicity was found. We provide proof-of-concept evidence for the efficacy and safety of this therapeutic strategy and anticipate that this TAT-TrkB peptide has the potential to be a disease-modifying drug that can prevent and/or reverse cognitive deficits in patients with AD.
Indexed as
Alzheimer DiseaseBrain-Derived Neurotrophic FactorPeptidesReceptor, trkBAmyloid beta-PeptidesAnimalsDisease Models, AnimalFemaleHippocampusHumansMaleMembrane GlycoproteinsMiceMice, TransgenicNeuronal PlasticityProteolysisAmyloid beta-PeptidesBrain-Derived Neurotrophic FactorMembrane GlycoproteinsPeptidesReceptor, trkBAlzheimer’s diseaseamyloid βBDNFdrug screeninghippocampal plasticitylearningmemoryprotein cleavageTAT peptideTAT-TrkBTrkB receptor
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