Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease
Open accessAbstract
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-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β 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.
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Aβ deposition observed in brain regions devoid of microglia, including dura mater, choroid plexus, perivascular space.
“Aβ deposition can also be observed in regions of the brain devoid of microglia, including the dura mater, choroid plexus and perivascular space [71, 253]”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [71]
The ‘Dysfunctional lymphatics in amyloid pathology’ section reports Aβ deposition in the dura mater of Alzheimer’s disease patients. It does not establish deposition in the choroid plexus or perivascular space, or state that the listed sites are devoid of microglia; searches for those terms found no supporting passage. No page number is available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMicroglia may not be only cells contributing to Aβ plaque aggregation.
“suggesting that microglia may not be the only cells contributing to Aβ plaque aggregation”
From Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function (2022) · cites this paper as [71]
In “Dysfunctional lymphatics in amyloid pathology” (page not provided), the paper reports macrophages recruited to Aβ aggregates and increased hippocampal plaque load after meningeal lymphatic ablation. These findings support the suggestion that processes beyond microglia affect amyloid pathology, but they do not establish that macrophages or other cells contribute to plaque aggregation itself. (LLM, conf=0.82)
Experimental — accuracy not yet measuredVEGFC overexpression induced sprouting of meningeal lymphatic vessels and slowed cognitive decline in a mouse model of Alzheimer disease.
“VEGFC-overexpression induced spouting of the meningeal lymphatic vessels and slowed the cognitive decline in a mouse model of Alzheimer disease (50).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
Aging is associated with a steep fall in glymphatic flow in rodent and human brains.
“Aging is also associated with a steep fall in glymphatic flow in the brains of both rodents and humans.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
UV photoablation of meningeal lymphatic vessels and mechanical ligation of cervical lymphatics aggravated amyloid plaque formation in mouse models of Alzheimer disease.
“Conversely, both UV photoablation of meningeal lymphatic vessels and mechanical ligation of cervical lymphatics aggravated amyloid plaque formation in the same mouse models of Alzheimer disease (50, 51).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
Infusion of amyloid-β into CSF acutely reduces glymphatic activity in wild-type mice, suggesting a direct toxic effect.
“Infusion of amyloid-β into CSF acutely reduced glymphatic activity in wild-type mice suggesting a direct toxic effect (50, 55).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
CSF inflow of larger tracers is reduced by up to 85% in aged wild-type mice.
“CSF inflow of larger tracers are reduced by up to 85% in aged wild-type mice”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
Glymphatic CSF influx and CSF clearance are reduced in early amyloid deposition in the APP/PS1 Alzheimer disease model compared with littermate controls, and CSF clearance continues to decline as amyloid burden increases.
“glymphatic CSF influx and CSF clearance are each reduced in early stages of amyloid deposition in the APP/PS1 model of Alzheimer disease, compared with littermate controls; CSF clearance continues to decline as the amyloid burden increases (Fig. 1b).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
Contrast clearance in human brain tissue is inversely correlated with age in all subjects studied.
“while contrast clearance in human brain tissue was inversely correlated to age in all subjects studied (50, 52–54).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [50]
Alzheimer's disease involves accumulation of toxic amyloid-beta aggregates in the brain, partly because cleansing mechanisms progressively fail.
“Alzheimer’s disease (AD) is characterized by accumulation of toxic Aβ aggregates in the brain1, in part, due to progressive impairment of cleansing mechanisms2–6.”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [4]
It may be possible to develop therapies that target both microglia and brain blood vasculature by modulating lymphatic vasculature function at the brain borders.
“Our data provided here suggests that it might be possible to devise strategies to therapeutically target both microglia and the brain blood vasculature, two important players in AD pathophysiology4,21,23,38–40, by modulating the function of the lymphatic vasculature at the brain borders.”
From Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy (2021) · cites this paper as [4]
Previous findings showing impairment of meningeal lymphatic function slows paravascular influx and efflux may suggest that impaired lymphatic clearance function exerts negative effect directly on accumulation of molecules within CSF, and upstream on molecular exit from brain into CSF.
“previous findings showing that impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain, as well as efflux from the interstitial space5, may suggest that impaired lymphatic clearance function may exert its negative effect directly on the accumulation of molecules within the CSF, and thereby further upstream on molecular exit from brain into CSF”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [5]
Impairment of meningeal lymphatic pathways slows paravascular efflux of amyloid-β from interstitial brain fluid.
“impairment of these meningeal lymphatic pathways has been shown to slow paravascular efflux of amyloid-β from interstitial brain fluid”
From Cerebrospinal fluid tracer efflux to parasagittal dura in humans (2020) · cites this paper as [5]
During sleep, the glymphatic system exchanges cerebrospinal fluid with interstitial fluid and clears amyloid-β.
“during sleep, the glymphatic system285 exchanges cerebrospinal fluid with interstitial fluid and clears Aβ286”
From Rhythms of life: circadian disruption and brain disorders across the lifespan (2019) · cites this paper as [286]
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- Authors
- Da Mesquita, S., Louveau, A., Vaccari, A., Smirnov, I., Cornelison, R. C., Kingsmore, K. M., Contarino, C., Onengut-Gumuscu, S., Farber, E., Raper, D., Viar, K. E., Powell, R. D., Baker, W., Dabhi, N., Bai, R., Cao, R., Hu, S., Rich, S. S., Munson, J. M., Lopes, M. B., Overall, C. C., Acton, S. T., & Kipnis, J.
- Affiliations
- University of Virginia (US)
- University of Trento (IT)
- University of Virginia Health System (US)
- Corresponding author
- Kipnis, Jonathan
- ORCID
- Venue
- Nature
- Published
- 2018-07-25
- Volume
- 560
- Issue
- 7717
- Pages
- 185-191
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6085146
- OpenAlex
- W2883628966
- Cited by
- 1,445
- References
- 64
- Citations by year
- 2026: 211 · 2025: 214 · 2024: 229 · 2023: 192 · 2022: 181 · 2021: 163 · 2020: 131 · 2019: 101 · 2018: 20 · 2017: 1
- FWCI
- 47.58
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-11-05)
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (RF1AG057496, R01AG034113, R37AG034113)
- National Cancer Institute (R37CA222563)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- meningeal lymphatic vessels, Alzheimer's disease, aging, cerebrospinal fluid, interstitial fluid, brain waste clearance, VEGF-C, amyloid-beta deposition, cognitive impairment, age-related cognitive decline, lymphatic drainage
- MeSH terms
- Aging, Alzheimer Disease, Amyloid, Animals, Brain, Cognition, Cognition Disorders, Disease Models, Animal, Female, Homeostasis, Humans, Lymph Nodes, Male, Meninges, Mice, Transgenic, Perfusion, Amyloid beta-Peptides, Lymphatic Vessels, Extracellular Fluid, Mice
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