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 decline in...

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Autores principales:	Raquel Sanchez-Varo, Elisabeth Sanchez-Mejias, Juan Jose Fernandez-Valenzuela, Vanessa De Castro, Marina Mejias-Ortega, Angela Gomez-Arboledas, Sebastian Jimenez, Maria Virtudes Sanchez-Mico, Laura Trujillo-Estrada, Ines Moreno-Gonzalez, David Baglietto-Vargas, Marisa Vizuete, Jose Carlos Davila, Javier Vitorica, Antonia Gutierrez
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Alzheimer’s disease synaptic pathology hippocampus transgenic mice (Tg) amyloid oligomers Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/8efa1e12f990456da15d700c8c5ad782
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spelling	oai:doaj.org-article:8efa1e12f990456da15d700c8c5ad7822021-11-04T08:48:59ZPlaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis1662-453X10.3389/fnins.2021.752594https://doaj.org/article/8efa1e12f990456da15d700c8c5ad7822021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fnins.2021.752594/fullhttps://doaj.org/toc/1662-453XAlzheimer’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.Raquel Sanchez-VaroRaquel Sanchez-VaroRaquel Sanchez-VaroElisabeth Sanchez-MejiasElisabeth Sanchez-MejiasJuan Jose Fernandez-ValenzuelaJuan Jose Fernandez-ValenzuelaVanessa De CastroMarina Mejias-OrtegaMarina Mejias-OrtegaAngela Gomez-ArboledasAngela Gomez-ArboledasSebastian JimenezSebastian JimenezSebastian JimenezMaria Virtudes Sanchez-MicoMaria Virtudes Sanchez-MicoMaria Virtudes Sanchez-MicoLaura Trujillo-EstradaLaura Trujillo-EstradaInes Moreno-GonzalezInes Moreno-GonzalezInes Moreno-GonzalezDavid Baglietto-VargasDavid Baglietto-VargasMarisa VizueteMarisa VizueteMarisa VizueteJose Carlos DavilaJose Carlos DavilaJavier VitoricaJavier VitoricaJavier VitoricaAntonia GutierrezAntonia GutierrezFrontiers Media S.A.articleAlzheimer’s diseasesynaptic pathologyhippocampustransgenic mice (Tg)amyloidoligomersNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease synaptic pathology hippocampus transgenic mice (Tg) amyloid oligomers Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	Alzheimer’s disease synaptic pathology hippocampus transgenic mice (Tg) amyloid oligomers Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Raquel Sanchez-Varo Raquel Sanchez-Varo Raquel Sanchez-Varo Elisabeth Sanchez-Mejias Elisabeth Sanchez-Mejias Juan Jose Fernandez-Valenzuela Juan Jose Fernandez-Valenzuela Vanessa De Castro Marina Mejias-Ortega Marina Mejias-Ortega Angela Gomez-Arboledas Angela Gomez-Arboledas Sebastian Jimenez Sebastian Jimenez Sebastian Jimenez Maria Virtudes Sanchez-Mico Maria Virtudes Sanchez-Mico Maria Virtudes Sanchez-Mico Laura Trujillo-Estrada Laura Trujillo-Estrada Ines Moreno-Gonzalez Ines Moreno-Gonzalez Ines Moreno-Gonzalez David Baglietto-Vargas David Baglietto-Vargas Marisa Vizuete Marisa Vizuete Marisa Vizuete Jose Carlos Davila Jose Carlos Davila Javier Vitorica Javier Vitorica Javier Vitorica Antonia Gutierrez Antonia Gutierrez Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
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.
format	article
author	Raquel Sanchez-Varo Raquel Sanchez-Varo Raquel Sanchez-Varo Elisabeth Sanchez-Mejias Elisabeth Sanchez-Mejias Juan Jose Fernandez-Valenzuela Juan Jose Fernandez-Valenzuela Vanessa De Castro Marina Mejias-Ortega Marina Mejias-Ortega Angela Gomez-Arboledas Angela Gomez-Arboledas Sebastian Jimenez Sebastian Jimenez Sebastian Jimenez Maria Virtudes Sanchez-Mico Maria Virtudes Sanchez-Mico Maria Virtudes Sanchez-Mico Laura Trujillo-Estrada Laura Trujillo-Estrada Ines Moreno-Gonzalez Ines Moreno-Gonzalez Ines Moreno-Gonzalez David Baglietto-Vargas David Baglietto-Vargas Marisa Vizuete Marisa Vizuete Marisa Vizuete Jose Carlos Davila Jose Carlos Davila Javier Vitorica Javier Vitorica Javier Vitorica Antonia Gutierrez Antonia Gutierrez
author_facet	Raquel Sanchez-Varo Raquel Sanchez-Varo Raquel Sanchez-Varo Elisabeth Sanchez-Mejias Elisabeth Sanchez-Mejias Juan Jose Fernandez-Valenzuela Juan Jose Fernandez-Valenzuela Vanessa De Castro Marina Mejias-Ortega Marina Mejias-Ortega Angela Gomez-Arboledas Angela Gomez-Arboledas Sebastian Jimenez Sebastian Jimenez Sebastian Jimenez Maria Virtudes Sanchez-Mico Maria Virtudes Sanchez-Mico Maria Virtudes Sanchez-Mico Laura Trujillo-Estrada Laura Trujillo-Estrada Ines Moreno-Gonzalez Ines Moreno-Gonzalez Ines Moreno-Gonzalez David Baglietto-Vargas David Baglietto-Vargas Marisa Vizuete Marisa Vizuete Marisa Vizuete Jose Carlos Davila Jose Carlos Davila Javier Vitorica Javier Vitorica Javier Vitorica Antonia Gutierrez Antonia Gutierrez
author_sort	Raquel Sanchez-Varo
title	Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis
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
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/8efa1e12f990456da15d700c8c5ad782
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Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

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