Immunotherapy against amyloid beta is modulated by meningeal lymphatic function VI
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE160220 | GEO | 2021/03/11
REPOSITORIES: GEO
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Project description:A growing body of evidence points to passive immunotherapy as a promising therapeutic strategy against AD. Herein, we show that meningeal lymphatic vasculature becomes dysfunctional in AD transgenic mice and that manipulating meningeal lymphatic drainage affects the outcome of anti-Aβ immunotherapy.
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Project description:A growing body of evidence points to passive immunotherapy as a promising therapeutic strategy against AD. Herein, we show that meningeal lymphatic vasculature becomes dysfunctional in AD transgenic mice and that manipulating meningeal lymphatic drainage affects the outcome of anti-Aβ immunotherapy.
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2021-03-11 | GSE141849 | GEO
Project description:A growing body of evidence points to passive immunotherapy as a promising therapeutic strategy against AD. Herein, we show that meningeal lymphatic vasculature becomes dysfunctional in AD transgenic mice and that manipulating meningeal lymphatic drainage affects the outcome of anti-Aβ immunotherapy.
2021-03-11 | GSE160219 | GEO
Project description:A growing body of evidence points to passive immunotherapy as a promising therapeutic strategy against AD. Herein, we show that meningeal lymphatic vasculature becomes dysfunctional in AD transgenic mice and that manipulating meningeal lymphatic drainage affects the outcome of anti-Aβ immunotherapy.
2021-03-11 | GSE160216 | GEO
Project description:Meningeal lymphatic vessels (mLVs) have been shown to be involved in amyloid beta (Aβ) clearance, which is considered as a potential therapeutic target for Alzheimer’s disease (AD). In this study, based on the superficial spatial distribution of mLVs, a near-infrared light is employed to modulate lymphatic drainage, significantly improving cognition of both aged and AD (5xFAD and APP/PS1) mice, and alleviating AD-associated pathology by reducing Aβ deposition, neuroinflammation and neuronal damage. Furthermore, transmission electron microscopy imaging and RNA sequencing data indicate amelioration of mitochondrial metabolism and cellular junction of meningeal lymphatic endothelial cells (mLECs) by light modulation. These studies collectively suggest that near-infrared light treatment can improve cognitive function by strengthening scavenging ability of mLVs through restoring mLEC function. In conclusion, lymphatic drainage potentiation by light promotes pathological remission and cognitive enhancement in aging and AD mouse models, which offers a potential amelioration strategy for neurodegenerative diseases.
2023-12-27 | GSE245658 | GEO
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217312 | GEO
Project description:The meningeal lymphatic network—housed within the dural meninges surrounding the brain— is critical for cerebrospinal fluid (CSF) drainage. Through continuous brain interstitial fluid (ISF) mixing with CSF via the glymphatic system, this lymphatic network facilitates the removal of central nervous system (CNS) waste. During aging and in Alzheimer’s disease (AD), attenuated meningeal lymphatic drainage promotes the buildup of toxic misfolded proteins—including amyloid beta—in the CNS. Alleviating this age-related meningeal lymphatic dysfunction represents a promising therapeutic strategy to alleviate AD pathology. However, the mechanisms underlying this lymphatic decline remain elusive. Here we demonstrate that age-related alterations in meningeal immunity contribute to meningeal lymphatic impairment. Single-cell RNA-sequencing of dural lymphatic endothelial cells in aged mice demonstrated a response signature to the cytokine IFNγ, which was elevated in the aged dura due to meningeal T cell accumulation. Chronic elevation of IFNγ in the meninges of young mice via AAV-mediated overexpression altered lymphatic adherans junctions and impaired CSF drainage to deep cervical lymph nodes—comparable to the deficits observed in aged mice. Direct disruption of lymphatic junctions via CSF-delivered VE-Cadherin disrupting antibodies was sufficient to phenocopy impairments in CSF drainage. Therapeutically, IFNγ neutralization in aged mice alleviated age-related impairments in meningeal lymphatic function. These data suggest manipulation of meningeal immunity as a viable therapeutic target to normalize CSF drainage in aged mice and alleviate the pathology in AD mice associated with impaired waste removal.
2023-03-10 | GSE217276 | GEO
Project description:The goal of this study is to use bulk RNA-sequencing of the right brain hemisphere to observe the effects of TBI in the context of pre-existing meningeal lymphatic dysfunction in mice. We find that pre-existing meningeal lymphatic dysfunction potentiates the inflammatory response to TBI, suggesting an important role for the meningeal lymphatics in injury site drainage and proper recovery.
2020-07-25 | GSE155063 | GEO
Project description:Aging is a major risk factor for many neurological pathologies, including Alzheimer’s disease (AD). However, the mechanisms underlying brain aging and cognitive decline remain elusive. Body tissues are perfused by interstitial fluid (ISF), which is locally reabsorbed via the lymphatic vascular network. In contrast, the parenchyma of the central nervous system (CNS) is devoid of lymphatic vasculature; in the brain, removal of cellular debris and toxic molecules, such as amyloid beta (A) peptides, is mediated by a combination of transcellular mechanisms of transport across the blood−brain and blood−cerebrospinal fluid (CSF) barriers, phagocytosis and digestion by resident microglia and recruited monocytes/macrophages, and CSF influx and ISF efflux through a paravascular route. The recent characterization of meningeal lymphatic vessels prompted a reassessment of the conventional pathways of CNS waste clearance. The role of this vasculature in brain function, specifically in the context of aging and AD, is still poorly understood. Here we show that meningeal lymphatic vessels play an essential role in maintaining brain homeostasis by draining macromolecules from the CNS (CSF and ISF) into the cervical lymph nodes. Using pharmacological, surgical, and genetic models we show that impairment of meningeal lymphatic function in adult mice slows paravascular influx of CSF macromolecules and efflux of ISF macromolecules, and induces cognitive impairment. Treatment with a lymphangiogenic factor, vascular endothelial growth factor C (VEGF-C), enhances meningeal lymphatic drainage of CSF macromolecules, improving brain perfusion and learning and memory performance in aged mice. Disruption of meningeal lymphatic vessels in transgenic mouse models of AD promotes amyloid deposition in the meninges, which closely correlates with human meningeal pathology, and aggravates overall disease severity. Our findings suggest that meningeal lymphatic dysfunction may be an aggravating factor in AD 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.
2018-08-03 | GSE104182 | GEO