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Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model
Synaptic functional disturbances with concomitant synapse loss represent central pathological hallmarks of Alzheimer’s disease. Excessive accumulation of cytotoxic amyloid oligomers is widely recognized as a key event that underlies neurodegeneration. Certain complement components are crucial instru...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671981/ https://www.ncbi.nlm.nih.gov/pubmed/32034429 http://dx.doi.org/10.1007/s00018-020-03468-0 |
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author | Györffy, Balázs A. Tóth, Vilmos Török, György Gulyássy, Péter Kovács, Réka Á. Vadászi, Henrietta Micsonai, András Tóth, Melinda E. Sántha, Miklós Homolya, László Drahos, László Juhász, Gábor Kékesi, Katalin A. Kardos, József |
author_facet | Györffy, Balázs A. Tóth, Vilmos Török, György Gulyássy, Péter Kovács, Réka Á. Vadászi, Henrietta Micsonai, András Tóth, Melinda E. Sántha, Miklós Homolya, László Drahos, László Juhász, Gábor Kékesi, Katalin A. Kardos, József |
author_sort | Györffy, Balázs A. |
collection | PubMed |
description | Synaptic functional disturbances with concomitant synapse loss represent central pathological hallmarks of Alzheimer’s disease. Excessive accumulation of cytotoxic amyloid oligomers is widely recognized as a key event that underlies neurodegeneration. Certain complement components are crucial instruments of widespread synapse loss because they can tag synapses with functional impairments leading to their engulfment by microglia. However, an exact understanding of the affected synaptic functions that predispose to complement-mediated synapse elimination is lacking. Therefore, we conducted systematic proteomic examinations on synaptosomes prepared from an amyloidogenic mouse model of Alzheimer’s disease (APP/PS1). Synaptic fractions were separated according to the presence of the C1q-tag using fluorescence-activated synaptosome sorting and subjected to proteomic comparisons. The results raised the decline of mitochondrial functions in the C1q-tagged synapses of APP/PS1 mice based on enrichment analyses, which was verified using flow cytometry. Additionally, proteomics results revealed extensive alterations in the level of septin protein family members, which are known to dynamically form highly organized pre- and postsynaptic supramolecular structures, thereby affecting synaptic transmission. High-resolution microscopy investigations demonstrated that synapses with considerable amounts of septin-3 and septin-5 show increased accumulation of C1q in APP/PS1 mice compared to the wild-type ones. Moreover, a strong positive correlation was apparent between synaptic septin-3 levels and C1q deposition as revealed via flow cytometry and confocal microscopy examinations. In sum, our results imply that deterioration of synaptic mitochondrial functions and alterations in the organization of synaptic septins are associated with complement-dependent synapse loss in Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03468-0) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7671981 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-76719812020-11-20 Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model Györffy, Balázs A. Tóth, Vilmos Török, György Gulyássy, Péter Kovács, Réka Á. Vadászi, Henrietta Micsonai, András Tóth, Melinda E. Sántha, Miklós Homolya, László Drahos, László Juhász, Gábor Kékesi, Katalin A. Kardos, József Cell Mol Life Sci Original Article Synaptic functional disturbances with concomitant synapse loss represent central pathological hallmarks of Alzheimer’s disease. Excessive accumulation of cytotoxic amyloid oligomers is widely recognized as a key event that underlies neurodegeneration. Certain complement components are crucial instruments of widespread synapse loss because they can tag synapses with functional impairments leading to their engulfment by microglia. However, an exact understanding of the affected synaptic functions that predispose to complement-mediated synapse elimination is lacking. Therefore, we conducted systematic proteomic examinations on synaptosomes prepared from an amyloidogenic mouse model of Alzheimer’s disease (APP/PS1). Synaptic fractions were separated according to the presence of the C1q-tag using fluorescence-activated synaptosome sorting and subjected to proteomic comparisons. The results raised the decline of mitochondrial functions in the C1q-tagged synapses of APP/PS1 mice based on enrichment analyses, which was verified using flow cytometry. Additionally, proteomics results revealed extensive alterations in the level of septin protein family members, which are known to dynamically form highly organized pre- and postsynaptic supramolecular structures, thereby affecting synaptic transmission. High-resolution microscopy investigations demonstrated that synapses with considerable amounts of septin-3 and septin-5 show increased accumulation of C1q in APP/PS1 mice compared to the wild-type ones. Moreover, a strong positive correlation was apparent between synaptic septin-3 levels and C1q deposition as revealed via flow cytometry and confocal microscopy examinations. In sum, our results imply that deterioration of synaptic mitochondrial functions and alterations in the organization of synaptic septins are associated with complement-dependent synapse loss in Alzheimer’s disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03468-0) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-02-07 2020 /pmc/articles/PMC7671981/ /pubmed/32034429 http://dx.doi.org/10.1007/s00018-020-03468-0 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Article Györffy, Balázs A. Tóth, Vilmos Török, György Gulyássy, Péter Kovács, Réka Á. Vadászi, Henrietta Micsonai, András Tóth, Melinda E. Sántha, Miklós Homolya, László Drahos, László Juhász, Gábor Kékesi, Katalin A. Kardos, József Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model |
title | Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model |
title_full | Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model |
title_fullStr | Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model |
title_full_unstemmed | Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model |
title_short | Synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an Alzheimer’s disease animal model |
title_sort | synaptic mitochondrial dysfunction and septin accumulation are linked to complement-mediated synapse loss in an alzheimer’s disease animal model |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671981/ https://www.ncbi.nlm.nih.gov/pubmed/32034429 http://dx.doi.org/10.1007/s00018-020-03468-0 |
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