Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.

TitleMeningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
Publication TypeJournal Article
Year of Publication2021
AuthorsDa Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FGeraldo, Wall M, Jiang H, Kodira CDilip, de Lima KAlves, Herz J, Louveau A, Goldman DH, Salvador AFrancesca, Onengut-Gumuscu S, Farber E, Dabhi N, Kennedy T, Milam MGrace, Baker W, Smirnov I, Rich SS, Benitez BA, Karch CM, Perrin RJ, Farlow M, Chhatwal JP, Holtzman DM, Cruchaga C, Harari O, Kipnis J
Corporate AuthorsDominantly Inherited Alzheimer Network
JournalNature
Volume593
Issue7858
Pagination255-260
Date Published2021 May
ISSN1476-4687
Abstract

Alzheimer's disease (AD) is the most prevalent cause of dementia. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain, 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.

DOI10.1038/s41586-021-03489-0
Alternate JournalNature
PubMed ID33911285
Grant ListR01 AG057777 / AG / NIA NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
UF1 AG032438 / AG / NIA NIH HHS / United States
R56 AG067764 / AG / NIA NIH HHS / United States
P30 AG066444 / AG / NIA NIH HHS / United States