Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Sandro Mesquita (), Zachary Papadopoulos, Taitea Dykstra, Logan Brase, Fabiana Geraldo Farias, Morgan Wall, Hong Jiang, Chinnappa Dilip Kodira, Kalil Alves Lima, Jasmin Herz, Antoine Louveau, Dylan H. Goldman, Andrea Francesca Salvador, Suna Onengut-Gumuscu, Emily Farber, Nisha Dabhi, Tatiana Kennedy, Mary Grace Milam, Wendy Baker, Igor Smirnov, Stephen S. Rich, Bruno A. Benitez, Celeste M. Karch, Richard J. Perrin, Martin Farlow, Jasmeer P. Chhatwal, David M. Holtzman, Carlos Cruchaga, Oscar Harari and Jonathan Kipnis ()
Additional contact information
Sandro Mesquita: University of Virginia
Zachary Papadopoulos: Washington University in St. Louis
Taitea Dykstra: Washington University in St. Louis
Logan Brase: Washington University in St. Louis
Fabiana Geraldo Farias: Washington University in St. Louis
Morgan Wall: University of Virginia
Hong Jiang: Washington University in St. Louis
Chinnappa Dilip Kodira: PureTech Health
Kalil Alves Lima: Washington University in St. Louis
Jasmin Herz: Washington University in St. Louis
Antoine Louveau: University of Virginia
Dylan H. Goldman: University of Virginia
Andrea Francesca Salvador: University of Virginia
Suna Onengut-Gumuscu: University of Virginia
Emily Farber: University of Virginia
Nisha Dabhi: University of Virginia
Tatiana Kennedy: University of Virginia
Mary Grace Milam: University of Virginia
Wendy Baker: University of Virginia
Igor Smirnov: University of Virginia
Stephen S. Rich: University of Virginia
Bruno A. Benitez: Washington University in St. Louis
Celeste M. Karch: Washington University in St. Louis
Richard J. Perrin: Washington University in St. Louis
Martin Farlow: Indiana School of Medicine
Jasmeer P. Chhatwal: Harvard Medical School, Department of Neurology
David M. Holtzman: Washington University in St. Louis
Carlos Cruchaga: Washington University in St. Louis
Oscar Harari: Washington University in St. Louis
Jonathan Kipnis: University of Virginia

Nature, 2021, vol. 593, issue 7858, 255-260

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03489-0

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