RESUMEN
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 (Aß) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aß 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-Aß passive immunotherapy by exacerbating the deposition of Aß, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aß 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.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Vasos Linfáticos/inmunología , Meninges/inmunología , Microglía/inmunología , Envejecimiento/efectos de los fármacos , Envejecimiento/inmunología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Animales , Anticuerpos Monoclonales Humanizados/inmunología , Encéfalo/irrigación sanguínea , Encéfalo/citología , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Modelos Animales de Enfermedad , Hipocampo/citología , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Masculino , Meninges/irrigación sanguínea , Meninges/citología , Ratones , Microglía/citología , Microglía/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor C de Crecimiento Endotelial Vascular/metabolismo , Factor C de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain ß-amyloid (Aß) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aß deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.