Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Author(s): Da Mesquita, S; Papadopoulos, Z; Dykstra, T; Brase, L; Farias, FG; Wall, M; Jiang, H; Kodira, CD; de Lima, KA; Herz, J; Louveau, A; Goldman, DH; Salvador, AF; Onengut-Gumuscu, S; Farber, E; Dabhi, N; Kennedy, T; Milam, MG; Baker, W; Smirnov, I; Rich, SS; Dominantly Inherited Alzheimer Network; Benitez, BA; Karch, CM; Perrin, RJ; Farlow, M; Chhatwal, JP; Holtzman, DM; Cruchaga, C; Harari, O; Kipnis, J;
Year: 2021;  
Journal: Nature;  
Volume: 593;  
Issue: 7858;  

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.