Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening
Alzheimer’s disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cyt...
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Nature Publishing Group
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643219/ |
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pubmed-46432192015-11-20 Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening Wood, Levi B. Winslow, Ashley R. Proctor, Elizabeth A. McGuone, Declan Mordes, Daniel A. Frosch, Matthew P. Hyman, Bradley T. Lauffenburger, Douglas A. Haigis, Kevin M. Article Alzheimer’s disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death. Nature Publishing Group 2015-11-13 /pmc/articles/PMC4643219/ /pubmed/26564777 http://dx.doi.org/10.1038/srep16622 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Wood, Levi B. Winslow, Ashley R. Proctor, Elizabeth A. McGuone, Declan Mordes, Daniel A. Frosch, Matthew P. Hyman, Bradley T. Lauffenburger, Douglas A. Haigis, Kevin M. |
| spellingShingle |
Wood, Levi B. Winslow, Ashley R. Proctor, Elizabeth A. McGuone, Declan Mordes, Daniel A. Frosch, Matthew P. Hyman, Bradley T. Lauffenburger, Douglas A. Haigis, Kevin M. Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening |
| author_facet |
Wood, Levi B. Winslow, Ashley R. Proctor, Elizabeth A. McGuone, Declan Mordes, Daniel A. Frosch, Matthew P. Hyman, Bradley T. Lauffenburger, Douglas A. Haigis, Kevin M. |
| author_sort |
Wood, Levi B. |
| title |
Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening |
| title_short |
Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening |
| title_full |
Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening |
| title_fullStr |
Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening |
| title_full_unstemmed |
Identification of neurotoxic cytokines by profiling Alzheimer’s disease tissues and neuron culture viability screening |
| title_sort |
identification of neurotoxic cytokines by profiling alzheimer’s disease tissues and neuron culture viability screening |
| description |
Alzheimer’s disease (AD) therapeutics based on the amyloid hypothesis have shown minimal efficacy in patients, suggesting that the activity of amyloid beta (Aβ) represents only one aspect of AD pathogenesis. Since neuroinflammation is thought to play an important role in AD, we hypothesized that cytokines may play a direct role in promoting neuronal death. Here, we profiled cytokine expression in a small cohort of human AD and control brain tissues. We identified AD-associated cytokines using partial least squares regression to correlate cytokine expression with quantified pathologic disease state and then used neuron cultures to test whether cytokines up-regulated in AD tissues could affect neuronal viability. This analysis identified cytokines that were associated with the pathological severity. Of the top correlates, only TNF-α reduced viability in neuron culture when applied alone. VEGF also reduced viability when applied together with Aβ, which was surprising because VEGF has been viewed as a neuro-protective protein. We found that this synthetic pro-death effect of VEGF in the context of Aβ was commensurate with VEGFR-dependent changes in multiple signaling pathways that govern cell fate. Our findings suggest that profiling of tissues combined with a culture-based screening approach can successfully identify new mechanisms driving neuronal death. |
| publisher |
Nature Publishing Group |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4643219/ |
| _version_ |
1613500628556840960 |