Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease
Abstract Alzheimer's disease (AD) is a predominant neurodegenerative disorder worldwide, with epileptic seizures being a common comorbidity that can exacerbate cognitive deterioration in affected individuals, thus highlighting the importance of early therapeutic intervention. It is determined t...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-06-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202417733 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849336989766123520 |
|---|---|
| author | Meng Jiang Qingqing Li Jianhui Chen Ruochong Li Jun Yao Yong Hu Haizheng Zhang Lixin Cai Maoguo Luo Yu Sun Wenwen Zeng |
| author_facet | Meng Jiang Qingqing Li Jianhui Chen Ruochong Li Jun Yao Yong Hu Haizheng Zhang Lixin Cai Maoguo Luo Yu Sun Wenwen Zeng |
| author_sort | Meng Jiang |
| collection | DOAJ |
| description | Abstract Alzheimer's disease (AD) is a predominant neurodegenerative disorder worldwide, with epileptic seizures being a common comorbidity that can exacerbate cognitive deterioration in affected individuals, thus highlighting the importance of early therapeutic intervention. It is determined that deletion of Ms4a4a, an AD‐associated gene, exacerbates seizures in amyloid β (Aβ)‐driven AD mouse model. MS4A4A is significantly upregulated in brain lesions in patients with epilepsy. Single‐cell sequencing reveals that MS4A4A is highly expressed in microglia within these lesions, linked to enhanced phagocytic activity. Mechanistic investigation delineates that deletion of Ms4a4a impairs microglial phagocytosis, accompanied by diminished calcium influx and disruptions in mitochondrial metabolic fitness. The cytosolic fragment of Ms4a4a is anchored to the cytoskeletal components, supporting its critical role in mediating phagocytosis. Induction of Ms4a4a through central delivery of LNP‐Il4 alleviates seizure conditions. Collectively, these findings identify Ms4a4a as a potential therapeutic target for managing seizures in AD treatment. |
| format | Article |
| id | doaj-art-aec7a2b7848340a887edbf53903d6ff7 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-aec7a2b7848340a887edbf53903d6ff72025-08-20T03:44:51ZengWileyAdvanced Science2198-38442025-06-011222n/an/a10.1002/advs.202417733Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's DiseaseMeng Jiang0Qingqing Li1Jianhui Chen2Ruochong Li3Jun Yao4Yong Hu5Haizheng Zhang6Lixin Cai7Maoguo Luo8Yu Sun9Wenwen Zeng10Institute for Immunology and School of Basic Medical Sciences and Beijing Key Laboratory of Immunological Research of Allergy (LIRA) Tsinghua University Beijing 100084 ChinaInstitute for Immunology and School of Basic Medical Sciences and Beijing Key Laboratory of Immunological Research of Allergy (LIRA) Tsinghua University Beijing 100084 ChinaInstitute for Immunology and School of Basic Medical Sciences and Beijing Key Laboratory of Immunological Research of Allergy (LIRA) Tsinghua University Beijing 100084 ChinaSchool of Life Sciences Tsinghua University Beijing 100084 ChinaENO Bio mRNA Innovation Institute Shenzhen Rhegen Biotechnology Co. Ltd Shenzhen 518000 ChinaENO Bio mRNA Innovation Institute Shenzhen Rhegen Biotechnology Co. Ltd Shenzhen 518000 ChinaSchool of Life Sciences Tsinghua University Beijing 100084 ChinaPediatric Epilepsy Center Peking University First Hospital Beijing 100034 ChinaSchool of Life Sciences Tsinghua University Beijing 100084 ChinaPediatric Epilepsy Center Peking University First Hospital Beijing 100034 ChinaInstitute for Immunology and School of Basic Medical Sciences and Beijing Key Laboratory of Immunological Research of Allergy (LIRA) Tsinghua University Beijing 100084 ChinaAbstract Alzheimer's disease (AD) is a predominant neurodegenerative disorder worldwide, with epileptic seizures being a common comorbidity that can exacerbate cognitive deterioration in affected individuals, thus highlighting the importance of early therapeutic intervention. It is determined that deletion of Ms4a4a, an AD‐associated gene, exacerbates seizures in amyloid β (Aβ)‐driven AD mouse model. MS4A4A is significantly upregulated in brain lesions in patients with epilepsy. Single‐cell sequencing reveals that MS4A4A is highly expressed in microglia within these lesions, linked to enhanced phagocytic activity. Mechanistic investigation delineates that deletion of Ms4a4a impairs microglial phagocytosis, accompanied by diminished calcium influx and disruptions in mitochondrial metabolic fitness. The cytosolic fragment of Ms4a4a is anchored to the cytoskeletal components, supporting its critical role in mediating phagocytosis. Induction of Ms4a4a through central delivery of LNP‐Il4 alleviates seizure conditions. Collectively, these findings identify Ms4a4a as a potential therapeutic target for managing seizures in AD treatment.https://doi.org/10.1002/advs.202417733Alzheimer's diseaseepilepsymicrogliaMS4A4Aphagocytosis |
| spellingShingle | Meng Jiang Qingqing Li Jianhui Chen Ruochong Li Jun Yao Yong Hu Haizheng Zhang Lixin Cai Maoguo Luo Yu Sun Wenwen Zeng Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease Advanced Science Alzheimer's disease epilepsy microglia MS4A4A phagocytosis |
| title | Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease |
| title_full | Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease |
| title_fullStr | Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease |
| title_full_unstemmed | Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease |
| title_short | Microglial MS4A4A Protects against Epileptic Seizures in Alzheimer's Disease |
| title_sort | microglial ms4a4a protects against epileptic seizures in alzheimer s disease |
| topic | Alzheimer's disease epilepsy microglia MS4A4A phagocytosis |
| url | https://doi.org/10.1002/advs.202417733 |
| work_keys_str_mv | AT mengjiang microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT qingqingli microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT jianhuichen microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT ruochongli microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT junyao microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT yonghu microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT haizhengzhang microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT lixincai microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT maoguoluo microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT yusun microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease AT wenwenzeng microglialms4a4aprotectsagainstepilepticseizuresinalzheimersdisease |