Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease

Wen, Yaru; Yang, Jiliang; Wang, Xiao; Ye, Zhibin

doi:10.4103/1673-5374.230299

Cited by 52 publications

(14 citation statements)

References 47 publications

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“…There has been intense focus on dural lymphatic vessels since their rediscovery in 2015 [144,145,160,162,179,[255][256][257][258][259][260]. Recent studies have found significant changes in CSF clearance, altered pathology in mouse models, or even cognitive defects, after ablation of the dural lymphatic vessels along the superior sagittal or transverse sinuses and it has been hypothesized that these effects are due to the dorsal lymphatic vessels playing a key role in CSF clearance and CNS immunosurveillance [179,255,259].…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics

Proulx

2021

Cell. Mol. Life Sci.

218

221

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Cerebrospinal fluid (CSF) is produced by the choroid plexuses within the ventricles of the brain and circulates through the subarachnoid space of the skull and spinal column to provide buoyancy to and maintain fluid homeostasis of the brain and spinal cord. The question of how CSF drains from the subarachnoid space has long puzzled scientists and clinicians. For many decades, it was believed that arachnoid villi or granulations, outcroppings of arachnoid tissue that project into the dural venous sinuses, served as the major outflow route. However, this concept has been increasingly challenged in recent years, as physiological and imaging evidence from several species has accumulated showing that tracers injected into the CSF can instead be found within lymphatic vessels draining from the cranium and spine. With the recent high-profile rediscovery of meningeal lymphatic vessels located in the dura mater, another debate has emerged regarding the exact anatomical pathway(s) for CSF to reach the lymphatic system, with one side favoring direct efflux to the dural lymphatic vessels within the skull and spinal column and another side advocating for pathways along exiting cranial and spinal nerves. In this review, a summary of the historical and contemporary evidence for the different outflow pathways will be presented, allowing the reader to gain further perspective on the recent advances in the field. An improved understanding of this fundamental physiological process may lead to novel therapeutic approaches for a wide range of neurological conditions, including hydrocephalus, neurodegeneration and multiple sclerosis.

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Section: Conclusion and Open Questionsmentioning

confidence: 99%

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics

Proulx

2021

Cell. Mol. Life Sci.

218

221

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“… 27 While meningeal LV anatomy is better understood, the functional role(s) of meningeal LVs appears to depend on the CNS disease. For example, ablation of meningeal LVs worsens pathology in a mouse model of Alzheimer’s disease, 28 but reduces pathology during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. 4 As little is known about the formation and function of meningeal LVs during stroke recovery, we investigated the development and relevance of new post-stroke LVs during long-term recovery. We determined that post-stroke meningeal lymphangiogenesis is dependent upon the method of ischemic infarction and does not occur after one the most commonly used preclinical stroke models, tMCAo.…”

Section: Discussionmentioning

confidence: 99%

Impaired meningeal lymphatic vessel development worsens stroke outcome

Yanev

Poinsatte

Hominick

et al. 2019

J Cereb Blood Flow Metab

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The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes.

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“…Recent studies have also tested the effects of boosting the function of the meningeal lymphatics in mouse models of AD. Intracisternal injection of recombinant human VEGF-C promoted dural lymphangiogenesis in 9-month-old APP/PS1 mice, reducing the levels of soluble Aβ 1–40 and Aβ 1–42 in the brain and CSF, and improving cognitive performance ( Wen et al, 2018 ). In a different study, delivery of a viral vector expressing mouse VEGF-C into the cisterna magna of J20 animals at 6–7 months of age did not improve the Aβ levels in the CSF, amyloid deposition in the hippocampus, or cognitive performance ( Da Mesquita et al, 2018b ).…”

Section: Role Of Meningeal Lymphatic (Dys)function In Neurological DImentioning

confidence: 99%

“…These discordant results might be explained by the different degrees of meningeal lymphatic vessel function or by the distinct kinetics of brain Aβ production and plaque development in APP/PS1 and J20 mice ( Mucke et al, 2000 ; Jankowsky et al, 2004 ). The different methods and regimens of VEGF-C delivery employed in each study ( Da Mesquita et al, 2018b ; Wen et al, 2018 ) might also explain the different outcomes. More experimental evidence is needed to better understand if and how VEGF-C treatment can be beneficial to treat AD-associated brain pathology and symptoms.…”

Section: Role Of Meningeal Lymphatic (Dys)function In Neurological DImentioning

confidence: 99%

CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

2021

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A genuine and functional lymphatic vascular system is found in the meninges that sheath the central nervous system (CNS). This unexpected (re)discovery led to a reevaluation of CNS fluid and solute drainage mechanisms, neuroimmune interactions and the involvement of meningeal lymphatics in the initiation and progression of neurological disorders. In this manuscript, we provide an overview of the development, morphology and unique functional features of meningeal lymphatics. An outline of the different factors that affect meningeal lymphatic function, such as growth factor signaling and aging, and their impact on the continuous drainage of brain-derived molecules and meningeal immune cells into the cervical lymph nodes is also provided. We also highlight the most recent discoveries about the roles of the CNS-draining lymphatic vasculature in different pathologies that have a strong neuroinflammatory component, including brain trauma, tumors, and aging-associated neurodegenerative diseases like Alzheimer’s and Parkinson’s. Lastly, we provide a critical appraisal of the conundrums, challenges and exciting questions involving the meningeal lymphatic system that ought to be investigated in years to come.

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Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease

Cited by 52 publications

References 47 publications

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics

Cerebrospinal fluid outflow: a review of the historical and contemporary evidence for arachnoid villi, perineural routes, and dural lymphatics

Impaired meningeal lymphatic vessel development worsens stroke outcome

CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges

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