Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Alzheimer's disease (AD) is the most prevalent cause of dementia(1). Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (A beta) is a promising therapeutic strategy(2,3). Meningeal lymphatic drainage has an important role in the accumulation of A beta in the brain(4), 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-A beta passive immunotherapy by exacerbating the deposition of A beta, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of A beta 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.

Automated summary

The study found that the disappearance of meningeal lymphatic vessels worsened the outcomes of AD mice receiving immunotherapy targeting Aβ. However, therapeutic delivery of vascular endothelial growth factor C improved Aβ clearance. The gene signature of microglia with impaired meningeal lymphatic function in mice overlapped substantially with the transcriptional profile of activated microglia in AD patients.