Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
| العنوان: | Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy |
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| المؤلفون: | Jonathan Kipnis, Sandro Da Mesquita, Martin R. Farlow, Morgan Wall, David M. Holtzman, Emily Farber, Stephen S. Rich, Zachary Papadopoulos, Carlos Cruchaga, Andrea Francesca Salvador, Mary Grace Milam, Jasmeer P. Chhatwal, Bruno A. Benitez, Dylan H. Goldman, Fabiana H.G. Farias, Kalil Alves de Lima, Richard J. Perrin, Hong Jiang, Logan Brase, Chinnappa D. Kodira, Antoine Louveau, Suna Onengut-Gumuscu, Jasmin Herz, Igor Smirnov, Wendy Baker, Nisha Dabhi, Tatiana Kennedy, Celeste M. Karch, Oscar Harari, Taitea Dykstra |
| المصدر: | Nature |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Aging, Pathology, medicine.medical_specialty, Transcription, Genetic, Amyloid beta, Meningeal lymphatic vessels, medicine.medical_treatment, Vascular Endothelial Growth Factor C, Antibodies, Monoclonal, Humanized, Microgliosis, Hippocampus, Article, Mice, 03 medical and health sciences, Meninges, 0302 clinical medicine, Alzheimer Disease, medicine, Animals, Humans, Lymphatic Vessels, Inflammation, Amyloid beta-Peptides, Multidisciplinary, Microglia, biology, business.industry, Brain, Immunotherapy, Disease Models, Animal, 030104 developmental biology, Lymphatic system, medicine.anatomical_structure, Neuroimmunology, Vascular endothelial growth factor C, biology.protein, business, 030217 neurology & neurosurgery |
| الوصف: | Alzheimer’s disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes. Meningeal lymphatic drainage can affect the microglial inflammatory response and anti-amyloid-β immunotherapy in mouse models of Alzheimer’s disease. |
| تدمد: | 1476-4687 0028-0836 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::af62472c1a3ebe4a90f571091c1679b1 https://doi.org/10.1038/s41586-021-03489-0 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....af62472c1a3ebe4a90f571091c1679b1 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 14764687 00280836 |
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