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dc.creatorGutiérrez Pérez, Antonia
dc.creatorVitorica Ferrández, Francisco Javier
dc.creatorDávila Cansino, José Carlos
dc.creatorVizuete Chacón, María Luisa
dc.creatorCarmona Cuenca, Irene
dc.creatorJiménez Muñoz, Sebastián
dc.creatorTrujillo Estrada, Laura Isabel
dc.creatorSánchez Varo, Raquel María
dc.creatorTorres Canalejo, Manuel
dc.creatorSánchez Mejías, Elisabeth
dc.creatorNavarro Garrido, Victoria
dc.date.accessioned2015-02-02T19:35:48Z
dc.date.available2015-02-02T19:35:48Z
dc.date.issued2012
dc.identifier.issn1750-1326es
dc.identifier.urihttp://hdl.handle.net/11441/18243
dc.description.abstractBackground: Axonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice. Results: Our data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes. Conclusion: A progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions.es
dc.language.isoenges
dc.relation.ispartofMolecular Neurodegeneration, 7 (59), 1-15.es
dc.rightsAtribución-NoComercial-SinDerivadas 4.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectAlzheimer’s diseasees
dc.subjectPS1/APP transgenic modelen
dc.subjectDystrophic neuritesen
dc.subjectTau phosphorylationen
dc.subjectCathepsin activity
dc.subjectAPP processingen
dc.subjectAbeta productionen
dc.titleDefective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampuses
dc.typeinfo:eu-repo/semantics/articlees
dc.rights.accessrightsinfo:eu-repo/semantics/openAccesses
dc.contributor.affiliationUniversidad de Sevilla. Departamento de Bioquímica y Biología Moleculares
dc.journaltitleMolecular Neurodegenerationes
dc.publication.volumen7es
dc.publication.issue59es
dc.publication.initialPage1es
dc.publication.endPage15es
dc.identifier.idushttps://idus.us.es/xmlui/handle/11441/18243

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