title: Modulation of BDNF cleavage by plasminogen-activator inhibitor-1 contributes to Alzheimer's neuropathology and cognitive deficits.
abstract: Brain-derived neurotrophic factor (BDNF) plays pivotal roles in neuronal function. The cleaved - mature - form of BDNF (mBDNF), predominantly expressed in adult brains, critically determines its effects. However, insufficient proteolytic processing under pathology may lead to the precursor form of BDNF (proBDNF) and thereby increased neuronal apoptosis and synaptic weakening. Previous findings in our lab showed that cognitive stimulation (CS) delayed memory decline in Tg2576 mouse model of Alzheimer's disease (AD), an effect that was tightly associated with augmented levels of mBDNF. In view of this association, the present study explored whether altered cleavage of BDNF could be involved in AD-related traits triggered by excessive amyloid-β (Aβ) pathology and whether this process could be therapeutically targeted. Aβ pathology, both in AD patient samples and experimental models, triggered the upregulation of plasminogen-activator inhibitor-1 (PAI-1) via JNK/c-Jun. This led to inhibition of plasmin-regulated conversion of mBDNF. Pharmacological inhibition of PAI-1 with PAI-039 sufficiently reverted Aβ-induced tau hyperphosphorylation and neurotoxicity. Chronic treatment of 15 old-month Tg2576 mice with oral administration of PAI-039 resulted in improved BDNF maturation and cognitive function without inducing significant changes in amyloid burden. In conclusion, upregulation of PAI-1 may be a critical mechanism underlying insufficient neurotrophic support and increased neurodegeneration associated with AD. Thus, targeting BDNF maturation through pharmacological inhibition of PAI-1 might become a potential treatment for AD.
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona, Spain; Department of Cellular and Molecular Neuropharmacology, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Gorka
authors.initials: G
authors.lastname: Gerenu
authors.affiliation: Department of Cellular and Molecular Neuropharmacology, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Martisova
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona, Spain.
authors.forename: Hilda
authors.initials: H
authors.lastname: Ferrero
authors.affiliation: Department of Cellular and Molecular Neuropharmacology, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carracedo
authors.affiliation: Faculty of Biological and Environmental Sciences, Department of Biosciences, Division of Physiology and Neuroscience, P.O. Box 65, FI-00014, University of Helsinki, Finland.
authors.forename: Tomi
authors.initials: T
authors.lastname: Rantamäki
authors.affiliation: Department of Pharmacology, University of Navarra, Pamplona, Spain.
authors.forename: Maria Javier
authors.initials: MJ
authors.lastname: Ramirez
authors.affiliation: Department of Cellular and Molecular Neuropharmacology, Division of Neuroscience, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; Department of Neuroscience, Biodonostia Health Research Institute, San Sebastian, Spain; Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Carlos III Health Institute, Ministry of Economy and Competitiveness, Spain; Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Stockholm, Sweden. Electronic address: francisco.gilbea@biodonostia.org.
authors.forename: Francisco Javier
authors.initials: FJ
authors.lastname: Gil-Bea
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D060825:Cognitive Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D058258:Serpin E2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; D058258:Serpin E2; C511869:Serpine2 protein, mouse; C488103:tiplaxtinin; C579455:BDNF protein, human
keywords: Beta-amyloid; Memory; Neurotrophin; Plasminogen; Tau hyperphosphorylation