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PubMed: 30046111

Title
Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease.
Journal
Nature
Volume
560
Issue
None
Pages
185-191
Date
2018-08-01
Authors
Da Mesquita S | Kipnis J | Acton ST | Bai R | Baker W | Cao R | Contarino C | Cornelison RC | Dabhi N | Farber E | Hu S | Kingsmore KM | Lopes MB | Louveau A | Munson JM | Onengut-Gumuscu S | Overall CC | Powell RD | Raper D | Rich SS | Smirnov I | Vaccari A | Viar KE

Evidence a73ba1180c
JSON

By contrast, the parenchyma of the CNS is devoid of lymphatic vasculature2; in the brain, removal of cellular debris and toxic molecules, such as amyloid-β peptides, is mediated by a combination of transcellular transport mechanisms across the blood−brain and blood−cerebrospinal fluid (CSF) barriers7–9, phagocytosis and digestion by resident microglia and recruited monocytes and/or macrophages10,11, as well as CSF influx and ISF efflux through a paravascular (glymphatic) route12–14

tloc(a(CHEBI:"amyloid-beta"), fromLoc(MESH:Blood), toLoc(MESH:"Cerebrospinal Fluid")) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

a(MESH:Macrophages) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

a(MESH:Microglia) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

a(MESH:Monocytes) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(GO:phagocytosis) regulates deg(a(CHEBI:"amyloid-beta")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

Evidence 01800d6961
JSON

Analysis of lymphoid and myeloid cell populations in the meninges (Extended Data Fig. 9d) demonstrated a significant increase in the number of macrophages upon lymphatic ablation compared to both control groups (Extended Data Fig. 9e), which might be correlated with increased amyloid-β deposition and inflammation in the meninges

a(CHEBI:"amyloid-beta") negativeCorrelation act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) negativeCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) decreases a(MESH:Macrophages) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) negativeCorrelation path(MESH:Inflammation) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

path(MESH:Inflammation) negativeCorrelation act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 8e463be75d
JSON

Staining for amyloid-β in the brains of nine patients with Alzheimer’s disease and eight controls without Alzheimer’s disease (Extended Data Table 1) revealed, as expected, marked parenchymal deposition of amyloid-β in the brains of patients with Alzheimer’s disease, but not in the brains of the controls without Alzheimer’s disease (Extended Data Fig. 9l, m)

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Parenchymal Tissue

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Brain
MeSH
Parenchymal Tissue

Evidence 5fd5307354
JSON

Notably, when compared to tissue from controls, all samples from patients with Alzheimer’s disease demonstrated striking vascular amyloid-β pathology in the cortical leptomeninges (Extended Data Fig. 9l, m) and amyloid-β deposition in the dura mater adjacent to the superior sagittal sinus (Fig. 3i, j) or further away from the sinus (Fig. 3k, l)

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dura Mater
MeSH
Superior Sagittal Sinus

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Dura Mater
MeSH
Superior Sagittal Sinus

Evidence f4ba5d7d2e
JSON

These findings showed that prominent meningeal amyloid-β deposition observed in patients with Alzheimer’s disease is also observed in mouse models of Alzheimer’s disease after meningeal lymphatic vessel ablation

a(CHEBI:"amyloid-beta") positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

a(MESH:"Lymphatic Vessels") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

path(MESH:"Alzheimer Disease") positiveCorrelation a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Meninges
MeSH
Alzheimer Disease

Evidence 1ec417cb2a
JSON

Macrophages in the dura of cases with Alzheimer’s disease were also found in close proximity to amyloid-β deposits (Fig. 3l)

a(CHEBI:"amyloid-beta") association a(MESH:Macrophages) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Dura Mater
MeSH
Alzheimer Disease

a(MESH:Macrophages) association a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Dura Mater
MeSH
Alzheimer Disease

Evidence def6c8b8dd
JSON

Together, three different models of impaired meningeal lymphatic function (pharmacological, surgical and genetic) showed a significant impact on brain perfusion by CSF macromolecules

tloc(a(CHEBI:macromolecule), fromLoc(GO:"extracellular space"), toLoc(MESH:"Intracellular Space")) association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Brain
MeSH
Cerebrospinal Fluid

act(a(MESH:"Lymphatic Vessels")) association tloc(a(CHEBI:macromolecule), fromLoc(GO:"extracellular space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Brain
MeSH
Cerebrospinal Fluid

act(a(MESH:"Lymphatic Vessels")) association bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(MESH:"Cerebrovascular Circulation") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

Evidence c0e5e8cf04
JSON

The use of this method resulted in effective ablation of meningeal lymphatic vessels (Fig. 1b, c), without any detectable off-target effects in the coverage of meningeal blood vasculature seven days after the procedure (Fig. 1d)

a(CHEBI:verteporfin) decreases a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 45a3cf25f6
JSON

A significant reduction in OVA-A647 drainage was observed in the visudyne with photoconversion group compared to the control groups (Extended Data Fig. 1b)

a(CHEBI:verteporfin) decreases act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence be88e15647
JSON

Brain perfusion by the CSF tracer was found to be significantly lower in the visudyne with photoconversion group than in the control groups (Fig. 1e, f and Extended Data Fig. 2f, g)

a(CHEBI:verteporfin) decreases bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

Evidence 7e227e770a
JSON

Notably, along with the lower influx of Gd into the parenchyma, we observed higher contrast in signal intensity (over approximately 52 min) in the ventricles of visudyne-treated mice, suggesting that Gd accumulation in the CSF occurred (Extended Data Fig. 3n)

a(CHEBI:verteporfin) decreases tloc(a(CHEBI:"gadolinium atom"), fromLoc(GO:"extracellular space"), toLoc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low

act(a(MESH:"Lymphatic Vessels")) increases tloc(a(CHEBI:"gadolinium atom"), fromLoc(GO:"extracellular space"), toLoc(MESH:"Cerebrospinal Fluid")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low

Evidence 6c9cb43ed1
JSON

Extracellular deposition of amyloid-β aggregates, the main constituent of senile plaques, is considered to be a pathological hallmark of Alzheimer’s disease that contributes to neuronal dysfunction and behavioural changes

a(HBP:HBP00018) positiveCorrelation path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

a(HBP:HBP00018) decreases bp(GO:"neuron cellular homeostasis") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

a(HBP:HBP00018) increases path(MESH:"Problem Behavior") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

path(MESH:"Alzheimer Disease") positiveCorrelation a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Extracellular Space

Evidence 7466e0fc99
JSON

The ageing-associated decrease in paravascular recirculation of CSF and ISF is thought to be responsible, at least in part, for the accumulation of amyloid-β in the brain parenchyma

act(a(HP:"interstitial fluid")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

bp(GO:"cerebrospinal fluid circulation") decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

bp(GO:aging) decreases bp(GO:"cerebrospinal fluid circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

bp(GO:aging) decreases act(a(HP:"interstitial fluid")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

bp(GO:aging) increases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

Evidence 80a5e9d311
JSON

Here we show that meningeal lymphatic vessels have an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (both CSF and ISF) into the cervical lymph nodes

a(MESH:"Lymphatic Vessels") regulates bp(MESH:Homeostasis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Meninges

a(MESH:"Lymphatic Vessels") increases tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Cerebrospinal Fluid"), toLoc(MESH:"Lymph Nodes")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges
MeSH
Neck

Evidence fccb0c3a21
JSON

These findings, as has been suggested previously, demonstrate that the efflux of parenchymal and/or ISF macromolecules and the drainage of these macromolecules into dCLNs are impaired as a consequence of meningeal lymphatic ablation, thus functionally connecting meningeal lymphatics with CSF influx and ISF efflux mechanisms

act(a(MESH:"Lymphatic Vessels")) increases tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Parenchymal Tissue"), toLoc(MESH:"Lymph Nodes")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges
MeSH
Neck

act(a(MESH:"Lymphatic Vessels")) increases tloc(a(CHEBI:macromolecule), fromLoc(HP:"interstitial fluid"), toLoc(MESH:"Lymph Nodes")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges
MeSH
Neck

Evidence 60a633ca98
JSON

Notably, the rate of tracer influx into the brain parenchyma was significantly increased as a result of enhanced meningeal lymphatic function (Fig. 2k, l and Extended Data Fig. 6q, r)

act(a(MESH:"Lymphatic Vessels")) increases tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Cerebrospinal Fluid"), toLoc(MESH:"Parenchymal Tissue")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence f5f9645638
JSON

Similar findings for brain perfusion by CSF were observed when meningeal lymphatic drainage was disrupted by surgical ligation of the vessels afferent to the dCLNs (Extended Data Fig. 3a–d)

act(a(MESH:"Lymphatic Vessels")) increases bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

Evidence 837c5b3b99
JSON

Prospero homeobox protein 1 heterozygous (Prox1+/−) mice, a genetic model of lymphatic vessel malfunction25, also presented impaired perfusion through the brain parenchyma and impaired CSF drainage (Extended Data Fig. 3e–i)

act(a(MESH:"Lymphatic Vessels")) increases bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

act(a(MESH:"Lymphatic Vessels")) increases bp(GO:"cerebrospinal fluid secretion") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Parenchymal Tissue

Evidence 40ff67d0c8
JSON

The increased drainage after VEGF-C treatment in old mice also correlated with enhanced brain perfusion by CSF macromolecules (Extended Data Fig. 7f, g)

act(a(MESH:"Lymphatic Vessels")) positiveCorrelation bp(MESH:"Cerebrovascular Circulation") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

bp(MESH:"Cerebrovascular Circulation") positiveCorrelation act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain

Evidence bf1db5da20
JSON

A significant difference between control groups and visudyne with photoconversion group was observed in the cued test of the CFC (Extended Data Fig. 5e, f), which points to an impairment in fear memory and in hippocampal– amygdala neuronal circuitry in mice with impaired meningeal lymphatic vessel function

act(a(MESH:"Lymphatic Vessels")) increases bp(GO:"fear response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence ed81de2cd2
JSON

Mice with ablated meningeal lymphatic vessels also showed significant deficits in spatial learning in the MWM (Fig. 1k–o)

act(a(MESH:"Lymphatic Vessels")) increases path(MESH:"Spatial Learning") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence bcc8eb778e
JSON

Similar impairments in spatial learning and memory were observed in mice that had undergone lymphatic ligation (Extended Data Fig. 5g–j), supporting the notion that the observed effect is a result of dysfunctional meningeal lymphatic drainage and not an artefact of the ablation method using visudyne

act(a(MESH:"Lymphatic Vessels")) increases path(MESH:"Spatial Learning") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence c99d2c9719
JSON

Significant transcriptional alterations were also associated with excitatory synaptic remodelling and plasticity, hippocampal neuronal transmission, learning and memory and ageing-related cognitive decline (Extended Data Fig. 5q, r)

act(a(MESH:"Lymphatic Vessels")) increases bp(GO:memory) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) association bp(GO:"excitatory chemical synaptic transmission") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) increases bp(GO:learning) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) association bp(GO:"neuronal signal transduction") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus

bp(GO:"excitatory chemical synaptic transmission") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:"neuronal signal transduction") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus

Evidence c78f3ffa8e
JSON

However, significant differences in hippocampal gene expression were found in response to MWM performance after prolonged meningeal lymphatic ablation (Extended Data Fig. 5m, n)

act(a(MESH:"Lymphatic Vessels")) association bp(GO:"gene expression") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Hippocampus
MeSH
Meninges

bp(GO:"gene expression") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Medium
MeSH
Hippocampus
MeSH
Meninges

Evidence 9fcbd9a6df
JSON

Notably, although the fold change in significantly altered genes after lymphatic ablation and MWM was moderate (−1.79 < log2(fold change) < 1.69), functional enrichment analysis (Extended Data Fig. 5o, p) revealed changes in gene sets associated with neurodegenerative diseases, such as Huntington’s, Parkinson’s and Alzheimer’s disease (Extended Data Fig. 5o)

act(a(MESH:"Lymphatic Vessels")) association path(MESH:"Huntington Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) association path(MESH:"Parkinson Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) association path(MESH:"Alzheimer Disease") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

path(MESH:"Alzheimer Disease") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

path(MESH:"Huntington Disease") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

path(MESH:"Parkinson Disease") association act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 7b4fa544be
JSON

Furthermore, different gene sets that are involved in the regulation of metabolite generation and processing, glycolysis and mitochondrial respiration and oxidative stress were also significantly altered in the hippocampus upon lymphatic ablation and performance of the behaviour test (Extended Data Fig. 5p, s–v)

act(a(MESH:"Lymphatic Vessels")) regulates a(CHEBI:metabolite) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) regulates bp(MESH:Glycolysis) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) regulates bp(GO:"response to oxidative stress") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) regulates bp(GO:"cellular respiration") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Mitochondria
Confidence
High
MeSH
Hippocampus
MeSH
Meninges

Evidence 5e741c4264
JSON

The reported findings that ageing is also associated with peripheral lymphatic dysfunction led us to hypothesize that the deterioration of meningeal lymphatic vessels underlies some aspects of age-associated cognitive decline

act(a(MESH:"Lymphatic Vessels")) negativeCorrelation bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

bp(GO:aging) negativeCorrelation act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence dd06e089a0
JSON

Collectively, these data point to no apparent meningeal lymphatic dysfunction in transgenic mice with Alzheimer’s disease at younger ages, which might explain the inefficacy of mVEGF-C treatment

act(a(MESH:"Lymphatic Vessels")) increases act(p(MGI:Vegfc)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges
MeSH
Alzheimer Disease

Evidence 0a53cc86b3
JSON

However, 5xFAD mice with ablated meningeal lymphatic vessels demonstrated marked deposition of amyloid-β in the meninges (Fig. 3b), as well as macrophage recruitment to large amyloid-β aggregates (Fig. 3c)

act(a(MESH:"Lymphatic Vessels")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) decreases bp(GO:"macrophage migration") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 4db20abf03
JSON

Notably, along with meningeal amyloid-β pathology, we observed an aggravation of brain amyloid-β burden in the hippocampi of 5xFAD mice with dysfunctional meningeal lymphatic vessels (Fig. 3d–g)

act(a(MESH:"Lymphatic Vessels")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Hippocampus
MeSH
Meninges

Evidence 9d4507679f
JSON

A similar outcome was observed in J20 transgenic mice after a total of three months of meningeal lymphatic ablation (Extended Data Fig. 9f); amyloid-β aggregates had formed in the meninges (Extended Data Fig. 9g) and the amyloid-β plaque load in the hippocampi of these mice was significantly increased (Extended Data Fig. 9h–k)

act(a(MESH:"Lymphatic Vessels")) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

act(a(MESH:"Lymphatic Vessels")) decreases a(HBP:HBP00018) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence bc0dddfa00
JSON

Enrichment analysis revealed, however, changes in gene sets involved in immune and inflammatory responses, phospholipid metabolism, extracellular matrix organization, cellular adhesion and endothelial tube morphogenesis, all of which suggest that there are functional alterations in meningeal LECs with age (Fig. 2c).

bp(GO:"extracellular matrix organization") association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:"cell adhesion") association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:"endothelial tube morphogenesis") association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:"immune response") association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:"inflammatory response") association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:"phospholipid metabolic process") association bp(GO:aging) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) association bp(GO:"immune response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) association bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) association bp(GO:"phospholipid metabolic process") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) association bp(GO:"extracellular matrix organization") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) association bp(GO:"cell adhesion") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) association bp(GO:"endothelial tube morphogenesis") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 5098ac9a9a
JSON

Ageing also leads to progressive lymphatic vessel dysfunction in peripheral tissues

bp(GO:aging) decreases act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence 406d64928e
JSON

Indeed, and in agreement with a previous study, old mice demonstrate reduced brain perfusion by CSF macromolecules compared to young counterparts (Extended Data Fig. 6a, b)

bp(GO:aging) decreases tloc(a(CHEBI:macromolecule), fromLoc(GO:"extracellular space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebrospinal Fluid

Evidence c64b793bc1
JSON

The altered expression of genes involved in the transmembrane receptor protein tyrosine kinase signalling pathway in old mice, namely the downregulation of Cdk5r1, Adamts3 and Fgfr3, indicated possible changes in signalling by lymphangiogenic growth factors in old meningeal LECs (Fig. 2d)

bp(GO:aging) decreases p(MGI:Cdk5r1) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) decreases p(MGI:Adamts3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(GO:aging) decreases p(MGI:Fgfr3) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence f5c8896d1d
JSON

Impaired brain perfusion by CSF in old mice was accompanied by a decrease in meningeal lymphatic vessel diameter and coverage, as well as decreased drainage of CSF macromolecules into dCLNs in both females and males (Extended Data Fig. 6c–f)

bp(MESH:"Cerebrovascular Circulation") increases act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

bp(MESH:"Cerebrovascular Circulation") increases tloc(a(CHEBI:macromolecule), fromLoc(GO:"extracellular space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebrospinal Fluid

Evidence eaeee45204
JSON

Transcranial delivery (through a thinned skull surface) of hydrogel-encapsulated VEGF-C peptide also resulted in increased diameter of meningeal lymphatics in young and old mice (Extended Data Fig. 7a–c)

composite(a(CHEBI:"poly(ethylene glycol dimethacrylate)"), p(MGI:Vegfc)) increases a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges

Evidence 04c47ae8cb
JSON

We have previously shown that treatment with recombinant VEGF-C increases the diameter of meningeal lymphatic vessels

p(MGI:Vegfc) increases a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges

Evidence 9cf3ea6f0f
JSON

Furthermore, delivery of VEGF-C by adenoviral gene therapy was previously found to efficiently boost peripheral lymphatic sprouting and function

p(MGI:Vegfc) increases act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 66b0aa7417
JSON

Treatment of young mice with AAV1-CM-mVEGF-C resulted in a significant increase in meningeal lymphatic vessel diameter, without affecting blood vessel coverage (Extended Data Fig. 6k–m)

p(MGI:Vegfc) increases a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges

Evidence c133280018
JSON

Treatment of old mice (at 20–24 months) with AAV1-CMV-mVEGF-C also resulted in increased lymphatic vessel diameter (compared to AAV1-CMV-eGFP) without detectable off-target effects on the meningeal blood vasculature coverage and on meningeal and/or brain vascular haemodynamics (Fig. 2e–h and Extended Data Fig. 6n–p)

p(MGI:Vegfc) increases a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges

Evidence eaadf93626
JSON

This VEGF-C treatment led to a significant increase in the function of meningeal lymphatic vessels in old mice, whereas young–adult mice did not respond to the treatment (Extended Data Fig. 7d, e), probably due to the ceiling effect of their existing capacity to drain OVA-A647

p(MGI:Vegfc) increases act(a(MESH:"Lymphatic Vessels")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

Evidence 71e07104df
JSON

Moreover, viral expression of mVEGF-C did not significantly affect the diameter of meningeal lymphatic vessels, the level of amyloid-β in the CSF, or amyloid-β deposition in the hippocampus (Extended Data Fig. 8g–n)

p(MGI:Vegfc) causesNoChange a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges
MeSH
Alzheimer Disease

p(MGI:Vegfc) causesNoChange a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebrospinal Fluid
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence 9440436922
JSON

However, AAV1-CMV-mVEGF-C treatment resulted in significant improvement in the latency to platform and in the percentage of allocentric navigation strategies, in the MWM reversal at 12–14 months (Extended Data Fig. 7q, t) and in the MWM acquisition and reversal at 20–22 months (Extended Data Fig. 7r, u), compared to AAV1-CMV-eGFP-treated age-matched mice

p(MGI:Vegfc) increases path(MESH:"Spatial Learning") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence d2d2b9976c
JSON

Increased expression of VEGF-C in the adult brain has previously been shown to boost proliferation of neural stem cells in the hippocampus

p(MGI:Vegfc) increases bp(GO:"stem cell proliferation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neuron
Confidence
Medium
MeSH
Hippocampus

Evidence 4f1e00a266
JSON

The beneficial effect of mVEGF-C treatment in mice from the sham group, which performed significantly better in the NLR (Fig. 2n, o) and MWM (Fig. 2p–r) tests, was abrogated in mice in which the CSF-draining lymphatic vessels had been ligated

p(MGI:Vegfc) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High

Evidence f5cb9e7825
JSON

Accordingly, the drainage of CSF macromolecules into dCLNs was significantly higher in sham-operated mice treated with mVEGF-C compared to all other groups (Fig. 2s, t)

p(MGI:Vegfc) increases tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Cerebrospinal Fluid"), toLoc(MESH:"Lymph Nodes")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Neck

Evidence 31e1df92b6
JSON

Independently of the model, the level of CSF tracer drained into the dCLNs was comparable between transgenic mice with Alzheimer’s disease and age-matched wild-type littermates (Extended Data Fig. 8p–s)

p(MGI:Vegfc) causesNoChange tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Cerebrospinal Fluid"), toLoc(MESH:"Lymph Nodes")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Cerebrospinal Fluid
MeSH
Hippocampus
MeSH
Alzheimer Disease

Evidence eb69ae0396
JSON

Similarly, the morphology and coverage of meningeal lymphatic vessels did not differ between wild-type and 5xFAD mice at 3–4 months of age (Extended Data Fig. 8t, u)

p(MGI:Vegfc) causesNoChange path(HP:"Abnormal lymphatic vessel morphology") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges
MeSH
Alzheimer Disease

Evidence 80ec31b82c
JSON

Within the brain parenchyma, it was shown that aquaporin 4 (AQP4) expression by astrocytes plays an important role in the modulation of paravascular CSF macromolecule influx and efflux (through the glymphatic route)

p(MGI:Aqp4) regulates tloc(a(CHEBI:macromolecule), fromLoc(GO:"extracellular space"), toLoc(MESH:"Intracellular Space")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Parenchymal Tissue

p(MGI:Aqp4) regulates tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Intracellular Space"), toLoc(GO:"extracellular space")) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Brain
MeSH
Cerebrospinal Fluid
MeSH
Parenchymal Tissue

Evidence be933189ef
JSON

Deletion of Aqp4 in transgenic mice with Alzheimer’s disease also resulted in increased amyloid-β plaque burden and exacerbated cognitive impairment

p(MGI:Aqp4) decreases a(CHEBI:"amyloid-beta") View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

p(MGI:Aqp4) increases bp(GO:cognition) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Alzheimer Disease

Evidence 3b0306ee7c
JSON

Treatment with VEGF-C156S resulted in a significant increase in meningeal lymphatic diameter (Extended Data Fig. 7i, j), drainage of tracer from the CSF (Extended Data Fig. 7k, l), and paravascular influx of tracer into the brains of old mice (Extended Data Fig. 7m, n)

p(MGI:Vegfc, var("p.Cys156Ser")) increases a(MESH:"Lymphatic Vessels") View Subject | View Object

Appears in Networks:
Annotations
Confidence
Low
MeSH
Meninges

p(MGI:Vegfc, var("p.Cys156Ser")) increases tloc(a(CHEBI:macromolecule), fromLoc(MESH:"Cerebrospinal Fluid"), toLoc(MESH:Brain)) View Subject | View Object

Appears in Networks:
Annotations
Confidence
High
MeSH
Meninges

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.