Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.
Sandro Da MesquitaZachary PapadopoulosTaitea DykstraLogan BraseFabiana Geraldo FariasMorgan WallHong JiangChinnappa Dilip KodiraKalil Alves de LimaJasmin HerzAntoine LouveauDylan H GoldmanAndrea Francesca SalvadorSuna Onengut-GumuscuEmily FarberNisha DabhiTatiana KennedyMary Grace MilamWendy BakerIgor SmirnovStephen S Richnull nullBruno A BenitezCeleste M KarchRichard J PerrinMartin FarlowJasmeer P ChhatwalDavid M HoltzmanCarlos CruchagaOscar HarariJonathan KipnisPublished in: Nature (2021)
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.
Keyphrases
- inflammatory response
- lymph node
- vascular endothelial growth factor
- neuropathic pain
- lipopolysaccharide induced
- mouse model
- high fat diet induced
- lps induced
- toll like receptor
- gene expression
- magnetic resonance
- ultrasound guided
- machine learning
- spinal cord
- early onset
- type diabetes
- metabolic syndrome
- multiple sclerosis
- electronic health record
- magnetic resonance imaging
- computed tomography
- white matter
- brain injury
- copy number
- heat stress
- genome wide analysis