Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease

被引:1006
作者
Da Mesquita, Sandro [1 ,2 ]
Louveau, Antoine [1 ,2 ]
Vaccari, Andrea [3 ,4 ]
Smirnov, Igor [1 ,2 ]
Cornelison, R. Chase [4 ]
Kingsmore, Kathryn M. [4 ]
Contarino, Christian [1 ,2 ,5 ]
Onengut-Gumuscu, Suna [6 ]
Farber, Emily [6 ]
Raper, Daniel [1 ,2 ,7 ]
Viar, Kenneth E. [1 ,2 ]
Powell, Romie D. [1 ,2 ]
Baker, Wendy [1 ,2 ]
Dabhi, Nisha [1 ,2 ]
Bai, Robin [1 ,2 ]
Cao, Rui [4 ]
Hu, Song [4 ]
Rich, Stephen S. [6 ]
Munson, Jennifer M. [4 ,8 ]
Lopes, M. Beatriz [9 ]
Overall, Christopher C. [1 ,2 ]
Acton, Scott T. [3 ,4 ]
Kipnis, Jonathan [1 ,2 ]
机构
[1] Univ Virginia, Ctr Brain Immunol & Glia BIG, Charlottesville, VA 22904 USA
[2] Univ Virginia, Dept Neurosci, Charlottesville, VA 22904 USA
[3] Univ Virginia, Dept Elect & Comp Engn, Virginia Image & Video Anal Lab, Charlottesville, VA USA
[4] Univ Virginia, Dept Biomed Engn, Charlottesville, VA USA
[5] Univ Trento, Dept Math, Povo, Italy
[6] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA
[7] Univ Virginia Hlth Syst, Dept Neurosurg, Charlottesville, VA USA
[8] Virginia Tech, Coll Engn, Dept Biomed Engn & Mech, Blacksburg, VA USA
[9] Univ Virginia, Dept Pathol, Charlottesville, VA 22903 USA
基金
美国国家卫生研究院;
关键词
BRAIN INTERSTITIAL FLUID; GROWTH FACTOR-C; MOUSE MODELS; TRANSGENIC MICE; AMYLOID PROTEIN; GENE-THERAPY; BETA; EXPRESSION; MICROGLIA; SYSTEM;
D O I
10.1038/s41586-018-0368-8
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer's disease promotes amyloid-beta deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-beta accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer's disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.
引用
收藏
页码:185 / +
页数:27
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