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Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase
The pathology of Alzheimer’s disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ pro...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588676/ https://www.ncbi.nlm.nih.gov/pubmed/28877763 http://dx.doi.org/10.1186/s40478-017-0472-2 |
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author | Schweig, Jonas Elias Yao, Hailan Beaulieu-Abdelahad, David Ait-Ghezala, Ghania Mouzon, Benoit Crawford, Fiona Mullan, Michael Paris, Daniel |
author_facet | Schweig, Jonas Elias Yao, Hailan Beaulieu-Abdelahad, David Ait-Ghezala, Ghania Mouzon, Benoit Crawford, Fiona Mullan, Michael Paris, Daniel |
author_sort | Schweig, Jonas Elias |
collection | PubMed |
description | The pathology of Alzheimer’s disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Aβ-overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Aβ-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Aβ deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Aβ formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self-propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD. |
format | Online Article Text |
id | pubmed-5588676 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-55886762017-09-14 Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase Schweig, Jonas Elias Yao, Hailan Beaulieu-Abdelahad, David Ait-Ghezala, Ghania Mouzon, Benoit Crawford, Fiona Mullan, Michael Paris, Daniel Acta Neuropathol Commun Research The pathology of Alzheimer’s disease (AD) is characterized by dystrophic neurites (DNs) surrounding extracellular Aβ-plaques, microgliosis, astrogliosis, intraneuronal tau hyperphosphorylation and aggregation. We have previously shown that inhibition of the spleen tyrosine kinase (Syk) lowers Aβ production and tau hyperphosphorylation in vitro and in vivo. Here, we demonstrate that Aβ-overexpressing Tg PS1/APPsw, Tg APPsw mice, and tau overexpressing Tg Tau P301S mice exhibit a pathological activation of Syk compared to wild-type littermates. Syk activation is occurring in a subset of microglia and is age-dependently increased in Aβ-plaque-associated dystrophic neurites of Tg PS1/APPsw and Tg APPsw mice. In Tg Tau P301S mice, a pure model of tauopathy, activated Syk occurs in neurons that show an accumulation of misfolded and hyperphosphorylated tau in the cortex and hippocampus. Interestingly, the tau pathology is exacerbated in neurons that display high levels of Syk activation supporting a role of Syk in the formation of tau pathological species in vivo. Importantly, human AD brain sections show both pathological Syk activation in DNs around Aβ deposits and in neurons immunopositive for pathological tau species recapitulating the data obtained in transgenic mouse models of AD. Additionally, we show that Syk overexpression leads to increased tau accumulation and promotes tau hyperphosphorylation at multiple epitopes in human neuron-like SH-SY5Y cells, further supporting a role of Syk in the formation of tau pathogenic species. Collectively, our data show that Syk activation occurs following Aβ deposition and the formation of tau pathological species. Given that we have previously shown that Syk activation also promotes Aβ formation and tau hyperphosphorylation, our data suggest that AD pathological lesions may be self-propagating via a Syk dependent mechanism highlighting Syk as an attractive therapeutic target for the treatment of AD. BioMed Central 2017-09-06 /pmc/articles/PMC5588676/ /pubmed/28877763 http://dx.doi.org/10.1186/s40478-017-0472-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Schweig, Jonas Elias Yao, Hailan Beaulieu-Abdelahad, David Ait-Ghezala, Ghania Mouzon, Benoit Crawford, Fiona Mullan, Michael Paris, Daniel Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
title | Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
title_full | Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
title_fullStr | Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
title_full_unstemmed | Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
title_short | Alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
title_sort | alzheimer’s disease pathological lesions activate the spleen tyrosine kinase |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5588676/ https://www.ncbi.nlm.nih.gov/pubmed/28877763 http://dx.doi.org/10.1186/s40478-017-0472-2 |
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