a(MESH:"Lymphatic Vessels")
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 PubMed:30046111
Together, three different models of impaired meningeal lymphatic function (pharmacological, surgical and genetic) showed a significant impact on brain perfusion by CSF macromolecules PubMed:30046111
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) PubMed:30046111
A significant reduction in OVA-A647 drainage was observed in the visudyne with photoconversion group compared to the control groups (Extended Data Fig. 1b) PubMed:30046111
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) PubMed:30046111
However, significant differences in hippocampal gene expression were found in response to MWM performance after prolonged meningeal lymphatic ablation (Extended Data Fig. 5m, n) PubMed:30046111
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) PubMed:30046111
Ageing also leads to progressive lymphatic vessel dysfunction in peripheral tissues PubMed:30046111
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 PubMed:30046111
Together, three different models of impaired meningeal lymphatic function (pharmacological, surgical and genetic) showed a significant impact on brain perfusion by CSF macromolecules PubMed:30046111
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) PubMed:30046111
The increased drainage after VEGF-C treatment in old mice also correlated with enhanced brain perfusion by CSF macromolecules (Extended Data Fig. 7f, g) PubMed:30046111
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) PubMed:30046111
We have previously shown that treatment with recombinant VEGF-C increases the diameter of meningeal lymphatic vessels PubMed:30046111
Furthermore, delivery of VEGF-C by adenoviral gene therapy was previously found to efficiently boost peripheral lymphatic sprouting and function PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
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 PubMed:30046111
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 PubMed:30046111
Together, three different models of impaired meningeal lymphatic function (pharmacological, surgical and genetic) showed a significant impact on brain perfusion by CSF macromolecules PubMed:30046111
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 PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
Together, three different models of impaired meningeal lymphatic function (pharmacological, surgical and genetic) showed a significant impact on brain perfusion by CSF macromolecules PubMed:30046111
The increased drainage after VEGF-C treatment in old mice also correlated with enhanced brain perfusion by CSF macromolecules (Extended Data Fig. 7f, g) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
Mice with ablated meningeal lymphatic vessels also showed significant deficits in spatial learning in the MWM (Fig. 1k–o) PubMed:30046111
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 PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
However, significant differences in hippocampal gene expression were found in response to MWM performance after prolonged meningeal lymphatic ablation (Extended Data Fig. 5m, n) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
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 PubMed:30046111
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 PubMed:30046111
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) PubMed:30046111
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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.