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dc.contributor.authorFleitas Pérez, Catherine
dc.contributor.authorPiñol Ripoll, Gerard
dc.contributor.authorMarfull Oromí, Pau
dc.contributor.authorRocandio, Daniel
dc.contributor.authorFerrer, Isidre
dc.contributor.authorRampon, Claire
dc.contributor.authorEgea Navarro, Joaquim
dc.contributor.authorEspinet Mestre, Carme
dc.date.accessioned2019-01-17T10:17:15Z
dc.date.available2019-01-17T10:17:15Z
dc.date.issued2018
dc.identifier.issn1756-6606
dc.identifier.urihttp://hdl.handle.net/10459.1/65525
dc.description.abstractAlzheimer disease (AD) is a complex pathology related to multiple causes including oxidative stress. Brain-derived neurotrophic factor (BDNF) is a neutrotrophic factor essential for the survival and differentiation of neurons and is considered a key target in the pathophysiology of various neurodegenerative diseases, as for example AD. Contrarily to BDNF, the precursor form of BDNF (proBDNF) induces apoptosis through the specific interaction with p75 and its co-receptor, Sortilin. We used hippocampal tissue and cerebrospinal fluid from AD patients and controls. to study the localization and the levels of proBDNF, p75 and Sortilin as well as the post-traduccional modifications of proBDNF induced by Radical Oxygen Species, by immunofluorescence and Western blot. Differentiation and survival were assessed on differentiated mouse hippocampal neurons derived from postnatal neural stem cells from WT animals or from the transgenic AD animal model APP/PS1ΔE9, based on mutations of familiar AD. In AD patients we observe a significative increase of proBDNF and Sortilin expression and a significative increase of the ratio proBDNF/BDNF in their cerebrospinal fluid compared to controls. In addition, the proBDNF of AD patients is modified by ROS-derived advanced glycation end products, which prevent the processing of the proBDNF to the mature BDNF, leading to an increase of pathogenicity and a decrease of trophic effects. The cerebrospinal fluid from AD patients, but not from controls, induces apoptosis in differentiated hippocampal neurons mainly by the action of AGE-modified proBDNF present in the cerebrospinal fluid of the patients. This effect is triggered by the activation and processing of p75 that stimulate the internalization of the intracellular domain (ICD) within the nucleus causing apoptosis. Induction of apoptosis and p75 ICD internalization by AD patients-derived proBDNF is further enhanced in neuron cultures from the AD model expressing the APP/PS1ΔE9 transgene. Our results indicate the importance of proBDNF neurotoxic signaling in AD pathology essentially by three mechanisms: i) by an increase of proBDNF stability due to ROS-induced post-traductional modifications; ii) by the increase of expression of the p75 co-receptor, Sortilin and iii) by the increase of the basal levels of p75 processing found in AD.ca_ES
dc.description.sponsorshipThis work was supported by “Fundació La Marató 2015” (C.E.). We thank, IRBLleida Biobank (B.0000682), PLATAFORMA BIOBANCOS PT13/0010/0014, HUB-ICO-IDIBELL Biobank for providing human tissue and UAI IRBLleida for management support.ca_ES
dc.language.isoengca_ES
dc.publisherBMCca_ES
dc.relation.isformatofReproducció del document publicat a https://doi.org/10.1186/s13041-018-0411-6ca_ES
dc.relation.ispartofMolecular Brain, 2018, vol. 11, núm. 68, p. 1-16ca_ES
dc.rightscc-by (c) Catherine Fleitas et al., 2018ca_ES
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subjectAlzheimer’s diseaseca_ES
dc.subjectBiomarkersca_ES
dc.subjectBDNFca_ES
dc.subjectp75ca_ES
dc.titleproBDNF is modified by advanced glycation end products in Alzheimer’s disease and causes neuronal apoptosis by inducing p75 neurotrophin receptor processingca_ES
dc.typeinfo:eu-repo/semantics/articleca_ES
dc.identifier.idgrec029752
dc.type.versioninfo:eu-repo/semantics/publishedVersionca_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccessca_ES
dc.identifier.doihttps://doi.org/10.1186/s13041-018-0411-6


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cc-by (c) Catherine Fleitas et al., 2018
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