The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration
<jats:p>Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentrax...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Association for the Advancement of Science (AAAS)
2023
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| Online Access: | https://hdl.handle.net/1721.1/150035 |
| _version_ | 1826211744993771520 |
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| author | Zhou, Jiechao Wade, Sarah D Graykowski, David Xiao, Mei-Fang Zhao, Binhui Giannini, Lucia AA Hanson, Jesse E van Swieten, John C Sheng, Morgan Worley, Paul F Dejanovic, Borislav |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Zhou, Jiechao Wade, Sarah D Graykowski, David Xiao, Mei-Fang Zhao, Binhui Giannini, Lucia AA Hanson, Jesse E van Swieten, John C Sheng, Morgan Worley, Paul F Dejanovic, Borislav |
| author_sort | Zhou, Jiechao |
| collection | MIT |
| description | <jats:p>Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)–mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.</jats:p> |
| first_indexed | 2024-09-23T15:10:46Z |
| format | Article |
| id | mit-1721.1/150035 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:10:46Z |
| publishDate | 2023 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1500352023-04-01T03:11:25Z The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration Zhou, Jiechao Wade, Sarah D Graykowski, David Xiao, Mei-Fang Zhao, Binhui Giannini, Lucia AA Hanson, Jesse E van Swieten, John C Sheng, Morgan Worley, Paul F Dejanovic, Borislav Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences <jats:p>Complement overactivation mediates microglial synapse elimination in neurological diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but how complement activity is regulated in the brain remains largely unknown. We identified that the secreted neuronal pentraxin Nptx2 binds complement C1q and thereby regulates its activity in the brain. Nptx2-deficient mice show increased complement activity, C1q-dependent microglial synapse engulfment, and loss of excitatory synapses. In a neuroinflammation culture model and in aged TauP301S mice, adeno-associated virus (AAV)–mediated neuronal overexpression of Nptx2 was sufficient to restrain complement activity and ameliorate microglia-mediated synapse loss. Analysis of human cerebrospinal fluid (CSF) samples from a genetic FTD cohort revealed reduced concentrations of Nptx2 and Nptx2-C1q protein complexes in symptomatic patients, which correlated with elevated C1q and activated C3. Together, these results show that Nptx2 regulates complement activity and microglial synapse elimination in the brain and that diminished Nptx2 concentrations might exacerbate complement-mediated neurodegeneration in patients with FTD.</jats:p> 2023-03-31T13:53:39Z 2023-03-31T13:53:39Z 2023-03-29 2023-03-31T13:41:21Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/150035 Zhou, Jiechao, Wade, Sarah D, Graykowski, David, Xiao, Mei-Fang, Zhao, Binhui et al. 2023. "The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration." Science Translational Medicine, 15 (689). en 10.1126/scitranslmed.adf0141 Science Translational Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) bioRxiv |
| spellingShingle | Zhou, Jiechao Wade, Sarah D Graykowski, David Xiao, Mei-Fang Zhao, Binhui Giannini, Lucia AA Hanson, Jesse E van Swieten, John C Sheng, Morgan Worley, Paul F Dejanovic, Borislav The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration |
| title | The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration |
| title_full | The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration |
| title_fullStr | The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration |
| title_full_unstemmed | The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration |
| title_short | The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration |
| title_sort | neuronal pentraxin nptx2 regulates complement activity and restrains microglia mediated synapse loss in neurodegeneration |
| url | https://hdl.handle.net/1721.1/150035 |
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