Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models
<jats:title>Abstract</jats:title><jats:p>Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau<jats:sup>P301S</jats:sup> synapse...
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2023
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| Online Access: | https://hdl.handle.net/1721.1/150029 |
| _version_ | 1826206850494758912 |
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| author | Dejanovic, Borislav Wu, Tiffany Tsai, Ming-Chi Graykowski, David Gandham, Vineela D Rose, Christopher M Bakalarski, Corey E Ngu, Hai Wang, Yuanyuan Pandey, Shristi Rezzonico, Mitchell G Friedman, Brad A Edmonds, Rose De Mazière, Ann Rakosi-Schmidt, Raphael Singh, Tarjinder Klumperman, Judith Foreman, Oded Chang, Michael C Xie, Luke Sheng, Morgan Hanson, Jesse E |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Dejanovic, Borislav Wu, Tiffany Tsai, Ming-Chi Graykowski, David Gandham, Vineela D Rose, Christopher M Bakalarski, Corey E Ngu, Hai Wang, Yuanyuan Pandey, Shristi Rezzonico, Mitchell G Friedman, Brad A Edmonds, Rose De Mazière, Ann Rakosi-Schmidt, Raphael Singh, Tarjinder Klumperman, Judith Foreman, Oded Chang, Michael C Xie, Luke Sheng, Morgan Hanson, Jesse E |
| author_sort | Dejanovic, Borislav |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau<jats:sup>P301S</jats:sup> synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau<jats:sup>P301S</jats:sup> hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in Tau<jats:sup>P301S</jats:sup> mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene <jats:italic>Trem2</jats:italic> impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.</jats:p> |
| first_indexed | 2024-09-23T13:39:31Z |
| format | Article |
| id | mit-1721.1/150029 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:39:31Z |
| publishDate | 2023 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1500292023-04-01T03:27:26Z Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models Dejanovic, Borislav Wu, Tiffany Tsai, Ming-Chi Graykowski, David Gandham, Vineela D Rose, Christopher M Bakalarski, Corey E Ngu, Hai Wang, Yuanyuan Pandey, Shristi Rezzonico, Mitchell G Friedman, Brad A Edmonds, Rose De Mazière, Ann Rakosi-Schmidt, Raphael Singh, Tarjinder Klumperman, Judith Foreman, Oded Chang, Michael C Xie, Luke Sheng, Morgan Hanson, Jesse E Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences <jats:title>Abstract</jats:title><jats:p>Microglia and complement can mediate neurodegeneration in Alzheimer’s disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in Tau<jats:sup>P301S</jats:sup> synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in Tau<jats:sup>P301S</jats:sup> hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte–synapse association and decreased astrocytic and microglial synapses engulfment in Tau<jats:sup>P301S</jats:sup> mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene <jats:italic>Trem2</jats:italic> impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.</jats:p> 2023-03-30T18:47:12Z 2023-03-30T18:47:12Z 2022 2023-03-30T18:40:53Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/150029 Dejanovic, Borislav, Wu, Tiffany, Tsai, Ming-Chi, Graykowski, David, Gandham, Vineela D et al. 2022. "Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models." Nature Aging, 2 (9). en 10.1038/S43587-022-00281-1 Nature Aging Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Dejanovic, Borislav Wu, Tiffany Tsai, Ming-Chi Graykowski, David Gandham, Vineela D Rose, Christopher M Bakalarski, Corey E Ngu, Hai Wang, Yuanyuan Pandey, Shristi Rezzonico, Mitchell G Friedman, Brad A Edmonds, Rose De Mazière, Ann Rakosi-Schmidt, Raphael Singh, Tarjinder Klumperman, Judith Foreman, Oded Chang, Michael C Xie, Luke Sheng, Morgan Hanson, Jesse E Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models |
| title | Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models |
| title_full | Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models |
| title_fullStr | Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models |
| title_full_unstemmed | Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models |
| title_short | Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer’s disease mouse models |
| title_sort | complement c1q dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in alzheimer s disease mouse models |
| url | https://hdl.handle.net/1721.1/150029 |
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