Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Mesquita, Sandro Dá; Papadopoulos, Zachary; Dykstra, Taitea; Brase, Logan; Farias, Fabiana; Wall, Morgan; Jiang, Hong; Kodira, Chinnappa D.; Lima, Kalil Alves de; Herz, Jasmin; Louveau, Antoine; Goldman, Dylan H.; Salvador, Andrea Francesca; Önengüt-Gümüşcü, Suna; Farber, Emily; Dabhi, Nisha; Kennedy, Tatiana; Milam, Mary Grace; Baker, Wendy; Smirnov, Igor; Rich, Stephen S.; Benitez, Bruno A.; Karch, Celeste M.; Perrin, Richard J.; Farlow, Martin R.; Chhatwal, Jasmeer P.; Holtzman, David M.; Cruchaga, Carlos; Harari, Oscar; Kipnis, Jonathan

doi:10.1038/s41586-021-03489-0

Cited by 251 publications

(278 citation statements)

References 70 publications

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“…Although previous studies have shown that rTMS may suppress the expression of APP and APP cleavage enzyme, β-secretase 1 (BACE1), therefore reduce the production and processing of Aβ in the AD mouse brains [ 27 ], however, merely reducing Aβ production may not be sufficient for the pathological improvement and cognitive benefits observed in rTMS-treated AD animal models and patients. Our results now provide evidences showing that, concomitant with reduced Aβ deposits in multiple brain regions as compared with untreated 5xFAD mice, two weeks of high frequency rTMS regime also significantly prevented the decline of cognitive function, likely through the improved drainage efficiency through the glymphatic system and meningeal lymphatics, which may facilitate the clearance of interstitial Aβ as suggested by recent studies [ 14 , 16 , 29 , 30 , 67 ]. Therefore, the therapeutic effects of rTMS on preventing the progression of Aβ pathology in the AD brains are likely two-fold: on one hand by suppressing Aβ production, and on the other hand by enhancing clearance of extracellular Aβ, rendering it an effective treatment for early stage AD.…”

Section: Discussionsupporting

confidence: 80%

Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease

Lin

Jin

et al. 2021

acta neuropathol commun

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high prevalence rate among the elderly population. A large number of clinical studies have suggested repetitive transcranial magnetic stimulation (rTMS) as a promising non-invasive treatment for patients with mild to moderate AD. However, the underlying cellular and molecular mechanisms remain largely uninvestigated. In the current study, we examined the effect of high frequency rTMS treatment on the cognitive functions and pathological changes in the brains of 4- to 5-month old 5xFAD mice, an early pathological stage with pronounced amyloidopathy and cognitive deficit. Our results showed that rTMS treatment effectively prevented the decline of long-term memories of the 5xFAD mice for novel objects and locations. Importantly, rTMS treatment significantly increased the drainage efficiency of brain clearance pathways, including the glymphatic system in brain parenchyma and the meningeal lymphatics, in the 5xFAD mouse model. Significant reduction of Aβ deposits, suppression of microglia and astrocyte activation, and prevention of decline of neuronal activity as indicated by the elevated c-FOS expression, were observed in the prefrontal cortex and hippocampus of the rTMS-treated 5xFAD mice. Collectively, these findings provide a novel mechanistic insight of rTMS in regulating brain drainage system and β-amyloid clearance in the 5xFAD mouse model, and suggest the potential use of the clearance rate of contrast tracer in cerebrospinal fluid as a prognostic biomarker for the effectiveness of rTMS treatment in AD patients.

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Section: Discussionsupporting

confidence: 80%

Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease

Lin

Jin

et al. 2021

acta neuropathol commun

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“…It is possible that the impairment of the glymphatic flow and resultant accumulation of cytokines [ 93 ] and metabolic wastes create a vicious cycle to perpetuate neuroinflammation (see Figure 2 ). In the context of meningeal lymphatic vessels, recent work showed that ablation of drainage through the meningeal lymphatic vessels in a mouse model of Alzheimer’s disease exacerbated amyloid-β deposition, neurovascular dysfunction, microgliosis, and behavioral deficits [ 94 ]. Interestingly, microglia changed towards a more inflammatory phenotype when meningeal lymphatic vessels were ablated [ 94 ].…”

Section: How Does Neuroinflammation Affect the Glymphatic System?mentioning

confidence: 99%

“…In the context of meningeal lymphatic vessels, recent work showed that ablation of drainage through the meningeal lymphatic vessels in a mouse model of Alzheimer’s disease exacerbated amyloid-β deposition, neurovascular dysfunction, microgliosis, and behavioral deficits [ 94 ]. Interestingly, microglia changed towards a more inflammatory phenotype when meningeal lymphatic vessels were ablated [ 94 ]. These findings underscore our hypothesis that an impairment of the brain’s drainage system accelerates the neuroinflammatory response, probably due to the accumulation or entrapment of waste and pro-inflammatory cytokines within the brain.…”

Section: How Does Neuroinflammation Affect the Glymphatic System?mentioning

confidence: 99%

The Glymphatic System (En)during Inflammation

Mogensen

Delle

2021

IJMS

112

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The glymphatic system is a fluid-transport system that accesses all regions of the brain. It facilitates the exchange of cerebrospinal fluid and interstitial fluid and clears waste from the metabolically active brain. Astrocytic endfeet and their dense expression of the aquaporin-4 water channels promote fluid exchange between the perivascular spaces and the neuropil. Cerebrospinal and interstitial fluids are together transported back to the vascular compartment by meningeal and cervical lymphatic vessels. Multiple lines of work show that neurological diseases in general impair glymphatic fluid transport. Insofar as the glymphatic system plays a pseudo-lymphatic role in the central nervous system, it is poised to play a role in neuroinflammation. In this review, we discuss how the association of the glymphatic system with the meningeal lymphatic vessel calls for a renewal of established concepts on the CNS as an immune-privileged site. We also discuss potential approaches to target the glymphatic system to combat neuroinflammation.

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“…The apparently selective response of the meningeal and lacteal lymphatics to VEGFC/D/R3 modulating agents during adulthood may provide the opportunity to intervene in this pathway therapeutically with minimal off-target effects. Recent studies in mice have highlighted the benefits of promoting lymphangiogenesis of the meningeal lymphatic vessels in increasing the efficacy of checkpoint inhibitor treatment for glioblastoma [ 99 ], and promoting the clearance of amyloid β in a mouse model of Alzheimer’s disease via immunotherapy with anti-amyloid β (Aβ) antibodies [ 100 ]. In a similar vein, delivery of VEGFC to cardiac tissue has been demonstrated to promote lymphangiogenesis and the clearance of tissue fluid and inflammation, reducing fibrosis and improving regeneration in mouse [ 101 , 102 ], rat [ 103 ] and zebrafish [ 104 ] models of cardiac injury.…”

Section: Vegfc/vegfd/vegfr3 Signalling In Lymphatic Vascular Diseasementioning

confidence: 99%

Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update

Secker

Harvey

2021

IJMS

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The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.

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Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy

Cited by 251 publications

References 70 publications

Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease

Repetitive transcranial magnetic stimulation increases the brain’s drainage efficiency in a mouse model of Alzheimer’s disease

The Glymphatic System (En)during Inflammation

Regulation of VEGFR Signalling in Lymphatic Vascular Development and Disease: An Update

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