Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive declin...

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Autores: Sanchez-Varo, Raquel, Sanchez-Mejias, Elisabeth, Fernandez-Valenzuela, Juan Jose, De Castro, Vanessa, Mejias-Ortega, Marina, Gomez-Arboledas, Angela, Jimenez, Sebastian, Sanchez-Mico, Maria Virtudes, Trujillo-Estrada, Laura, Moreno-Gonzalez, Ines, Baglietto-Vargas, David, Vizuete, Marisa, Davila, Jose Carlos, Vitorica, Javier, Gutierrez, Antonia
Tipo de documento: artigo
Data de publicação:2021
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositório:Repisalud
Idioma:inglês
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/18497
Acesso em linha:http://hdl.handle.net/20.500.12105/18497
Access Level:Acceso aberto
Palavra-chave:Alzheimer’s disease
Synaptic pathology
Hippocampus
Transgenic mice (Tg)
Amyloid
Oligomers
Enfermedad de Alzheimer
Hipocampo
Ratones transgénicos
Amiloide
Morfolinos
Humans
Infant
Plaque, Amyloid
Alzheimer Disease
Neurofibrillary Tangles
Presynaptic Terminals
Neurites
Astrocytes
Electrons
Microglia
Brain
Microscopy, Electron
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dc.title.none.fl_str_mv Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
title Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
spellingShingle Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
Sanchez-Varo, Raquel
Alzheimer’s disease
Synaptic pathology
Hippocampus
Transgenic mice (Tg)
Amyloid
Oligomers
Enfermedad de Alzheimer
Hipocampo
Ratones transgénicos
Amiloide
Morfolinos
Humans
Infant
Plaque, Amyloid
Alzheimer Disease
Neurofibrillary Tangles
Presynaptic Terminals
Neurites
Astrocytes
Electrons
Microglia
Brain
Hippocampus
Microscopy, Electron
title_short Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
title_full Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
title_fullStr Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
title_full_unstemmed Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
title_sort Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
dc.creator.none.fl_str_mv Sanchez-Varo, Raquel
Sanchez-Mejias, Elisabeth
Fernandez-Valenzuela, Juan Jose
De Castro, Vanessa
Mejias-Ortega, Marina
Gomez-Arboledas, Angela
Jimenez, Sebastian
Sanchez-Mico, Maria Virtudes
Trujillo-Estrada, Laura
Moreno-Gonzalez, Ines
Baglietto-Vargas, David
Vizuete, Marisa
Davila, Jose Carlos
Vitorica, Javier
Gutierrez, Antonia
author Sanchez-Varo, Raquel
author_facet Sanchez-Varo, Raquel
Sanchez-Mejias, Elisabeth
Fernandez-Valenzuela, Juan Jose
De Castro, Vanessa
Mejias-Ortega, Marina
Gomez-Arboledas, Angela
Jimenez, Sebastian
Sanchez-Mico, Maria Virtudes
Trujillo-Estrada, Laura
Moreno-Gonzalez, Ines
Baglietto-Vargas, David
Vizuete, Marisa
Davila, Jose Carlos
Vitorica, Javier
Gutierrez, Antonia
author_role author
author2 Sanchez-Mejias, Elisabeth
Fernandez-Valenzuela, Juan Jose
De Castro, Vanessa
Mejias-Ortega, Marina
Gomez-Arboledas, Angela
Jimenez, Sebastian
Sanchez-Mico, Maria Virtudes
Trujillo-Estrada, Laura
Moreno-Gonzalez, Ines
Baglietto-Vargas, David
Vizuete, Marisa
Davila, Jose Carlos
Vitorica, Javier
Gutierrez, Antonia
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv [Sanchez-Varo,R; Sanchez-Mejias,E; Fernandez-Valenzuela,JJ; De Castro,V; Mejias-Ortega,M; Gomez-Arboledas,A; Trujillo-Estrada,L; Moreno-Gonzalez,I; Baglietto-Vargas,D; Davila,JC; Gutierrez,A] Departamento Biologia Celular, Genetica y Fisiologia, Instituto de Investigacion Biomedica de Malaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain. [Sanchez-Varo,R; Sanchez-Mejias,E; Fernandez-Valenzuela,JJ; Mejias-Ortega,M; Gomez-Arboledas,A; Jimenez,S; Sanchez-Mico,MV; Trujillo-Estrada,L; Moreno-Gonzalez,I; Baglietto-Vargas,D; Vizuete,M; Davila,JC; Vitorica,J; Gutierrez,A] Centro de Investigación Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Sanchez-Varo,R] Departamento Fisiologia Humana, Histologia Humana, Anatomia Patologica y Educacion Fisica y Deportiva, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Jimenez,S; Sanchez-Mico,MV; Vizuete,M; Vitorica,J] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain. [Jimenez,S; Sanchez-Mico,MV; Vizuete,M; Vitorica,J] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio CSIC/Universidad de Sevilla, Seville, Spain. [Moreno-Gonzalez,I] Department of Neurology, McGovern Medical School, UTHealth Science Center at Houston, Houston, TX, United States
dc.subject.none.fl_str_mv Alzheimer’s disease
Synaptic pathology
Hippocampus
Transgenic mice (Tg)
Amyloid
Oligomers
Enfermedad de Alzheimer
Hipocampo
Ratones transgénicos
Amiloide
Morfolinos
Humans
Infant
Plaque, Amyloid
Alzheimer Disease
Neurofibrillary Tangles
Presynaptic Terminals
Neurites
Astrocytes
Electrons
Microglia
Brain
Hippocampus
Microscopy, Electron
topic Alzheimer’s disease
Synaptic pathology
Hippocampus
Transgenic mice (Tg)
Amyloid
Oligomers
Enfermedad de Alzheimer
Hipocampo
Ratones transgénicos
Amiloide
Morfolinos
Humans
Infant
Plaque, Amyloid
Alzheimer Disease
Neurofibrillary Tangles
Presynaptic Terminals
Neurites
Astrocytes
Electrons
Microglia
Brain
Hippocampus
Microscopy, Electron
description Alzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-11-04
2021
2021-11-04
2024
2024-02-19
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/18497
url http://hdl.handle.net/20.500.12105/18497
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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spelling Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology AnalysisSanchez-Varo, RaquelSanchez-Mejias, ElisabethFernandez-Valenzuela, Juan JoseDe Castro, VanessaMejias-Ortega, MarinaGomez-Arboledas, AngelaJimenez, SebastianSanchez-Mico, Maria VirtudesTrujillo-Estrada, LauraMoreno-Gonzalez, InesBaglietto-Vargas, DavidVizuete, MarisaDavila, Jose CarlosVitorica, JavierGutierrez, AntoniaAlzheimer’s diseaseSynaptic pathologyHippocampusTransgenic mice (Tg)AmyloidOligomersEnfermedad de AlzheimerHipocampoRatones transgénicosAmiloideMorfolinosHumansInfantPlaque, AmyloidAlzheimer DiseaseNeurofibrillary TanglesPresynaptic TerminalsNeuritesAstrocytesElectronsMicrogliaBrainHippocampusMicroscopy, ElectronAlzheimer's disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.Frontiers Media[Sanchez-Varo,R; Sanchez-Mejias,E; Fernandez-Valenzuela,JJ; De Castro,V; Mejias-Ortega,M; Gomez-Arboledas,A; Trujillo-Estrada,L; Moreno-Gonzalez,I; Baglietto-Vargas,D; Davila,JC; Gutierrez,A] Departamento Biologia Celular, Genetica y Fisiologia, Instituto de Investigacion Biomedica de Malaga-IBIMA, Facultad de Ciencias, Universidad de Málaga, Málaga, Spain. [Sanchez-Varo,R; Sanchez-Mejias,E; Fernandez-Valenzuela,JJ; Mejias-Ortega,M; Gomez-Arboledas,A; Jimenez,S; Sanchez-Mico,MV; Trujillo-Estrada,L; Moreno-Gonzalez,I; Baglietto-Vargas,D; Vizuete,M; Davila,JC; Vitorica,J; Gutierrez,A] Centro de Investigación Biomedica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. [Sanchez-Varo,R] Departamento Fisiologia Humana, Histologia Humana, Anatomia Patologica y Educacion Fisica y Deportiva, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. [Jimenez,S; Sanchez-Mico,MV; Vizuete,M; Vitorica,J] Departamento Bioquimica y Biologia Molecular, Facultad de Farmacia, Universidad de Sevilla, Seville, Spain. [Jimenez,S; Sanchez-Mico,MV; Vizuete,M; Vitorica,J] Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio CSIC/Universidad de Sevilla, Seville, Spain. [Moreno-Gonzalez,I] Department of Neurology, McGovern Medical School, UTHealth Science Center at Houston, Houston, TX, United States20242024-02-1920212021-11-0420212021-11-04research articlehttp://purl.org/coar/resource_type/c_2df8fbb1VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articlehttp://hdl.handle.net/20.500.12105/18497reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/184972026-06-12T12:43:37Z
score 15,812429

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