TY - JOUR
T1 - Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy
AU - Dominantly Inherited Alzheimer Network
AU - Da Mesquita, Sandro
AU - Papadopoulos, Zachary
AU - Dykstra, Taitea
AU - Brase, Logan
AU - Farias, Fabiana Geraldo
AU - Wall, Morgan
AU - Jiang, Hong
AU - Kodira, Chinnappa Dilip
AU - de Lima, Kalil Alves
AU - Herz, Jasmin
AU - Louveau, Antoine
AU - Goldman, Dylan H.
AU - Salvador, Andrea Francesca
AU - Onengut-Gumuscu, Suna
AU - Farber, Emily
AU - Dabhi, Nisha
AU - Kennedy, Tatiana
AU - Milam, Mary Grace
AU - Baker, Wendy
AU - Smirnov, Igor
AU - Rich, Stephen S.
AU - Benitez, Bruno A.
AU - Karch, Celeste M.
AU - Perrin, Richard J.
AU - Farlow, Martin
AU - Chhatwal, Jasmeer P.
AU - Holtzman, David M.
AU - Cruchaga, Carlos
AU - Harari, Oscar
AU - Kipnis, Jonathan
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/5/13
Y1 - 2021/5/13
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-021-03489-0
DO - 10.1038/s41586-021-03489-0
M3 - Article
C2 - 33911285
AN - SCOPUS:85105147927
SN - 0028-0836
VL - 593
SP - 255
EP - 260
JO - Nature
JF - Nature
IS - 7858
ER -