title: Early neuronal loss and axonal/presynaptic damage is associated with accelerated amyloid-β accumulation in AβPP/PS1 Alzheimer's disease mice subiculum.
abstract: The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss of synapses and neurons affecting particular cell subpopulations in selected brain areas, with the subiculum being one of the earliest regions displaying severe atrophy and pathology. The lack of significant neuronal loss in most AD models is, in fact, the major shortcoming for the preclinical evaluation of drugs that could have greater potential in patients to alleviate or prevent this disease. In this study, using immunohistochemical and stereological approaches, we have analyzed the histopathological events in the subiculum of AβPP751SwedLondon/PS1M146L mice, a transgenic model that displays neuronal vulnerability at early ages in hippocampus and entorhinal cortex. Our results indicate that the subiculum is the earliest affected region in the hippocampus, showing a selective early loss of both principal neurons (28%) and SOM-positive interneurons (69%). In addition, our data demonstrate the existence of an early axonal and synaptic pathology, which may represent the beginning of the synaptic disruption and loss. These neurodegenerative processes occur in parallel, and closely related, with the onset and accelerated progression of the extracellular amyloid-β deposition, thus suggesting plaques as major contributors of neuronal/axonal damage. Data reported here indicate that this AD model displays a selective AD-like neurodegenerative phenotype in highly vulnerable regions, including the subiculum, and therefore can be a very useful model for testing the therapeutic ability of potential compounds to protect neurons and ameliorate disease symptoms.
authors.affiliation: Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Trujillo-Estrada
authors.affiliation: Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Dávila
authors.affiliation: Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Sánchez-Mejias
authors.affiliation: Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Varo
authors.affiliation: Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Angela
authors.initials: A
authors.lastname: Gomez-Arboledas
authors.affiliation: Department Bioquímica y Biología Molecular, Facultad de Farmacia. Universidad de Sevilla, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain Instituto de Biomedicina de Sevilla (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
authors.forename: Marisa
authors.initials: M
authors.lastname: Vizuete
authors.affiliation: Department Bioquímica y Biología Molecular, Facultad de Farmacia. Universidad de Sevilla, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain Instituto de Biomedicina de Sevilla (IBIS)-Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Vitorica
authors.affiliation: Department Biología Celular, Genética y Fisiología, Facultad de Ciencias, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Spain Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Gutiérrez
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1
keywords: Alzheimer's disease; amyloid-β plaques; axonal damage; hippocampus; neuronal loss; subiculum; transgenic mice