Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy.

Autor: Da Mesquita S; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. damesquita@mayo.edu.; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. damesquita@mayo.edu., Papadopoulos Z; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.; Neuroscience Graduate Program, Washington University in St. Louis, St. Louis, MO, USA., Dykstra T; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA., Brase L; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA., Farias FG; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA., Wall M; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA., Jiang H; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Kodira CD; PureTech Health, Boston, MA, USA., de Lima KA; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA., Herz J; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA., Louveau A; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.; Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA., Goldman DH; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA., Salvador AF; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA., Onengut-Gumuscu S; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Farber E; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Dabhi N; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA., Kennedy T; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA., Milam MG; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA., Baker W; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA., Smirnov I; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA.; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA., Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Benitez BA; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Karch CM; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Perrin RJ; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA.; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Farlow M; Indiana School of Medicine, Indianapolis, IN, USA., Chhatwal JP; Massachusetts General Hospital, Harvard Medical School, Department of Neurology, Boston, MA, USA., Holtzman DM; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Cruchaga C; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA.; Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.; NeuroGenomics and Informatics Center, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA., Harari O; Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, USA., Kipnis J; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. kipnis@wustl.edu.; Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA. kipnis@wustl.edu.; Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, USA. kipnis@wustl.edu.; Neuroscience Graduate Program, Washington University in St. Louis, St. Louis, MO, USA. kipnis@wustl.edu.; Neuroscience Graduate Program, University of Virginia, Charlottesville, VA, USA. kipnis@wustl.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 May; Vol. 593 (7858), pp. 255-260. Date of Electronic Publication: 2021 Apr 28.
DOI: 10.1038/s41586-021-03489-0
Abstrakt: 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 (Aβ) is a promising therapeutic strategy 2,3 . Meningeal lymphatic drainage has an important role in the accumulation of Aβ 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-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.
Databáze: MEDLINE
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