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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...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2021
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600261/ https://www.ncbi.nlm.nih.gov/pubmed/34803589 http://dx.doi.org/10.3389/fnins.2021.752594 |
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author | 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_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_sort | Sanchez-Varo, Raquel |
collection | PubMed |
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 | Online Article Text |
id | pubmed-8600261 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86002612021-11-19 Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis 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 Front Neurosci Neuroscience 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. Frontiers Media S.A. 2021-11-04 /pmc/articles/PMC8600261/ /pubmed/34803589 http://dx.doi.org/10.3389/fnins.2021.752594 Text en Copyright © 2021 Sanchez-Varo, Sanchez-Mejias, Fernandez-Valenzuela, De Castro, Mejias-Ortega, Gomez-Arboledas, Jimenez, Sanchez-Mico, Trujillo-Estrada, Moreno-Gonzalez, Baglietto-Vargas, Vizuete, Davila, Vitorica and Gutierrez. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience 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 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 |
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_short | 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 |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8600261/ https://www.ncbi.nlm.nih.gov/pubmed/34803589 http://dx.doi.org/10.3389/fnins.2021.752594 |
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