Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2
Cadmium (Cd), a notorious environmental pollutant, has been linked to neurological disorders, but the underlying mechanism remains elusive. We aimed to explore the role of microglia in Cd-induced synaptic damages at environmentally relevant doses and whether microglia directly engulf synaptic struct...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-01-01
|
| Series: | Ecotoxicology and Environmental Safety |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651324016968 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823856920200478720 |
|---|---|
| author | Siyao Li Mingdan You Chengjie Chen Jingqi Fu Yuanyuan Xu Jingbo Pi Yi Wang |
| author_facet | Siyao Li Mingdan You Chengjie Chen Jingqi Fu Yuanyuan Xu Jingbo Pi Yi Wang |
| author_sort | Siyao Li |
| collection | DOAJ |
| description | Cadmium (Cd), a notorious environmental pollutant, has been linked to neurological disorders, but the underlying mechanism remains elusive. We aimed to explore the role of microglia in Cd-induced synaptic damages at environmentally relevant doses and whether microglia directly engulf synaptic structures. Nrf2 is deeply implicated in the status of microglial activation; therefore, we also investigated whether it is involved in the above process. Nrf2 knockout mice and wild-type mice were used to explore prolonged Cd exposure-induced synaptic damages, learning-memory impairments, and microglial activation. We also created Nrf2 knockdown (KD) BV2 microglia to investigate the role of cell-specific Nrf2 in Cd-induced microglial activation. Finally, we developed co-culture systems of either Nrf2-KD or Scramble microglia and primary neurons or HT22 neurons to study the effects of Nrf2-regulated microglial activation on synaptic damages induced by Cd. Moreover, the direct engulfment, a main avenue in microglia that may be responsible for Cd-induced synaptic damages and regulated by Nrf2, was specifically studied in vivo and in vitro, along with underlying specific mechanisms. We found that Cd exposure induced microglial overactivation, and Cd-overactivated microglia impaired synapses through direct engulfment of synaptic structures, which may contribute to learning-memory impairments. Both fractalkine and complement pathways underlay microglial engulfment of synapses due to Cd exposure. Nrf2 was essential in preventing microglial overactivation and subsequent direct engulfment, thus preventing the consequent synaptic damages due to Cd exposure. Overall, the findings suggest that Cd-overactivated microglia damage synapses through direct engulfment, resulting from the activation of fractalkine and complement pathways. |
| format | Article |
| id | doaj-art-9580aff6aba4442cb40f6c820cf5cf5d |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-9580aff6aba4442cb40f6c820cf5cf5d2025-02-12T05:30:01ZengElsevierEcotoxicology and Environmental Safety0147-65132025-01-01290117620Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2Siyao Li0Mingdan You1Chengjie Chen2Jingqi Fu3Yuanyuan Xu4Jingbo Pi5Yi Wang6Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110122, ChinaDepartment of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China; Key Laboratory of Environmental Pollution Monitoring & Disease Control, Ministry of Education (Guizhou Medical University), Guiyang, Guizhou 550025, ChinaKey Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China; Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, ChinaKey Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China; Department of Nutrition and Food Hygiene, School of Public Health, China Medical University, Shenyang, Liaoning 110122, ChinaKey Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China; Group of Chronic Disease and Environmental Genomics, School of Public Health, China Medical University, Shenyang, Liaoning 110122, ChinaKey Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China; Program of Environmental Toxicology, School of Public Health, China Medical University, Shenyang, Liaoning 110122, ChinaKey Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China; Department of Occupational and Environmental Health, School of Public Health, China Medical University, Shenyang, Liaoning 110122, China; Corresponding author at: Key Laboratory of Environmental Stress and Chronic Disease Control & Prevention, Ministry of Education (China Medical University), Shenyang, Liaoning 110122, China.Cadmium (Cd), a notorious environmental pollutant, has been linked to neurological disorders, but the underlying mechanism remains elusive. We aimed to explore the role of microglia in Cd-induced synaptic damages at environmentally relevant doses and whether microglia directly engulf synaptic structures. Nrf2 is deeply implicated in the status of microglial activation; therefore, we also investigated whether it is involved in the above process. Nrf2 knockout mice and wild-type mice were used to explore prolonged Cd exposure-induced synaptic damages, learning-memory impairments, and microglial activation. We also created Nrf2 knockdown (KD) BV2 microglia to investigate the role of cell-specific Nrf2 in Cd-induced microglial activation. Finally, we developed co-culture systems of either Nrf2-KD or Scramble microglia and primary neurons or HT22 neurons to study the effects of Nrf2-regulated microglial activation on synaptic damages induced by Cd. Moreover, the direct engulfment, a main avenue in microglia that may be responsible for Cd-induced synaptic damages and regulated by Nrf2, was specifically studied in vivo and in vitro, along with underlying specific mechanisms. We found that Cd exposure induced microglial overactivation, and Cd-overactivated microglia impaired synapses through direct engulfment of synaptic structures, which may contribute to learning-memory impairments. Both fractalkine and complement pathways underlay microglial engulfment of synapses due to Cd exposure. Nrf2 was essential in preventing microglial overactivation and subsequent direct engulfment, thus preventing the consequent synaptic damages due to Cd exposure. Overall, the findings suggest that Cd-overactivated microglia damage synapses through direct engulfment, resulting from the activation of fractalkine and complement pathways.http://www.sciencedirect.com/science/article/pii/S0147651324016968CadmiumMicrogliaDirect engulfmentNrf2Synapses |
| spellingShingle | Siyao Li Mingdan You Chengjie Chen Jingqi Fu Yuanyuan Xu Jingbo Pi Yi Wang Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2 Ecotoxicology and Environmental Safety Cadmium Microglia Direct engulfment Nrf2 Synapses |
| title | Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2 |
| title_full | Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2 |
| title_fullStr | Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2 |
| title_full_unstemmed | Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2 |
| title_short | Direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of Nrf2 |
| title_sort | direct engulfment of synapses by overactivated microglia due to cadmium exposure and the protective role of nrf2 |
| topic | Cadmium Microglia Direct engulfment Nrf2 Synapses |
| url | http://www.sciencedirect.com/science/article/pii/S0147651324016968 |
| work_keys_str_mv | AT siyaoli directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 AT mingdanyou directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 AT chengjiechen directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 AT jingqifu directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 AT yuanyuanxu directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 AT jingbopi directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 AT yiwang directengulfmentofsynapsesbyoveractivatedmicrogliaduetocadmiumexposureandtheprotectiveroleofnrf2 |