Drainage of senescent astrocytes from brain via meningeal lymphatic routes

Li, Qian; Chen, Yan; Feng, Weixi; Cai, Jiachen; Gao, Junying; Ge, Feifei; Zhou, Tong; Wang, Ze; Ding, Feng; Marshall, Charles; Chen, Sheng Di; Zhang, Yongjie; Sun, Mingkuan; Shi, Jingping; Xiao, Ming

doi:10.1016/j.bbi.2022.04.005

Cited by 29 publications

(23 citation statements)

References 78 publications

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“…Recently, the glymphatic system has been hypothesized to facilitate the clearance of senescent cells from the brain. This report highlights functional and structural connections between the glymphatic system and extracranial lymphatic drainage pathway as well the role of this mechanism in age-related diseases such as AD [ 35 ]. In this regard, the study of Li and collaborators revealed that clearance of senescent astrocytes through meningeal lymphatics depends on the vascular endothelial growth factor C (VEGF-C)/C-C motif chemokine ligand 21 (CCL21) pathway [ 35 ].…”

Section: The Glymphatic System Modelmentioning

confidence: 99%

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

et al. 2022

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Alzheimer’s disease (AD) is the most common cause of neurodegenerative dementia, whilst Parkinson’s disease (PD) is a neurodegenerative movement disorder. These two neurodegenerative disorders share the accumulation of toxic proteins as a pathological hallmark. The lack of definitive disease-modifying treatments for these neurogenerative diseases has led to the hypothesis of new pathogenic mechanisms to target and design new potential therapeutic approaches. The recent observation that the glymphatic system is supposed to be responsible for the movement of cerebrospinal fluid into the brain and clearance of metabolic waste has led to study its involvement in the pathogenesis of these classic proteinopathies. Aquaporin-4 (AQP4), a water channel located in the endfeet of astrocyte membrane, is considered a primary driver of the glymphatic clearance system, and defective AQP4-mediated glymphatic drainage has been linked to proteinopathies. The objective of the present review is to present the recent body of knowledge that links the glymphatic system to the pathogenesis of AD and PD disease and other lifestyle factors such as sleep deprivation and exercise that may influence glymphatic system function. We will also focus on the potential neuroimaging approaches that could identify a neuroimaging marker to detect glymphatic system changes.

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Section: The Glymphatic System Modelmentioning

confidence: 99%

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

et al. 2022

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“…Furthermore, single cell RNA‐seq reveals dramatic transcriptome changes of meningeal lymphatic ECs after aging, with downregulation on 377 genes, and upregulation of 230 57 . A recently published study has also reported that the meningeal lymphatics are an important route for clearance of senescent astrocytes from the brain during normal aging 197 . Understanding the dynamics of the brain borders environment during the aging process is fundamental, once aging is associated with different neurodegenerative pathologies.…”

Section: Meninges In Neurological Disordersmentioning

confidence: 99%

“…57 A recently published study has also reported that the meningeal lymphatics are an important route for clearance of senescent astrocytes from the brain during normal aging. 197 Understanding the dynamics of the brain borders environment during the aging process is fundamental, once aging is associated with different neurodegenerative pathologies.…”

Section: Aging/neurodegenerationmentioning

confidence: 99%

Neuroimmune signaling at the brain borders

Frederick

Tavares

Louveau

2022

Immunological Reviews

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The central nervous system has traditionally been viewed as an immune privilege site with increased tolerance towards antigens that would induce rejection and limited immune responses against CNS antigens. 1 Sir Peter Medawar established this concept when performing his transplantation experiments demonstrating delayed rejection of skin graft in the brain. 2 He postulated that the immune privilege function of the brain arose primarily from (i) lack of drainage of CNS antigens to mount immune responses; (ii) isolation of the brain from peripheral infiltration through the blood brain barrier; and (iii) the relative absence of antigen presenting cells within the CNS. However, further studies demonstrated that rather than isolation and ignorance of the CNS by the immune system, it is rather tightly regulated interactions between immune cells and the CNS that control the apparent immune privilege status of the brain. 3,4 Likely, these controlled interactions are in place to limit neuronal damages while ensuring protection of the brain from infections and facilitate tissue repair.The anatomical sites where most of these interactions appear to take place are particularly located at the borders of the CNS. While the brain parenchyma is virtually devoid of immune cells, with exception of microglia and mast cells, its borders are populated with numerous innate and adaptive immune cells that actively communicate with the periphery to ensure surveillance and protection of the CNS.Yet we still know very little about the establishment, maintenance, and function of these brain borders. New technical advances and a deeper understanding of neuroimmune interactions are driving the field toward the definition of compartmentalized interactions between the brain and the immune system to allow for synergic control and maintenance of brain function in health and disease.Here, we will discuss the establishment and maintenance of the three primary brain borders, the meninges, the choroid plexus, and the blood brain barrier. We then dive into the described roles of the

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“… 49 Senescent astroglial cells appear to be able to be physiologically cleared from the brain via para-vascular pathways (glymphatic pathways) to meningeal lymphatic pathways. 63 The meningeal lymphatic vessels and the glymphatic system are being now studied as therapeutic targets to remove macromolecules, debris, and senescent or damaged cells. 61 , 62 Pharmacologically, these senescent cells can be eliminated by “senolytic cocktails .” 49 , 54 …”

Section: Potential Strategies To Combat Ad Based On Modifying the Act...mentioning

confidence: 99%

“… 49 , 53 , 55 , 59 All the studies above-mentioned suggest that the elimination or control of these senescent cells may be an effective strategy to combat neurodegeneration (ie the clearance of senescent cells prevents Tau-dependent pathology in AD mouse models 49 or the removal of senescent NG2+ cells improves the AD pathology. 54 Senescent astroglial cells appear to be able to be physiologically cleared from the brain via para-vascular pathways (glymphatic pathways 60 - 62 to meningeal lymphatic pathways, 63 but senescent microglial or oligodendrocyte cell clearance systems are not well known. However, it seems that these senescent cells can be eliminated by “senolytic cocktails.” 49 , 54 …”

Section: Introductionmentioning

confidence: 99%

The relationships between neuroglial and neuronal changes in Alzheimer’s disease, and the related controversies II: gliotherapies and multimodal therapy

Toledano-Dı́az¹,

Álvarez

Toledano

2022

J Cent Nerv Syst Dis

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Since the original description of Alzheimer´s disease (AD), research into this condition has mainly focused on assessing the alterations to neurons associated with dementia, and those to the circuits in which they are involved. In most of the studies on human brains and in many models of AD, the glial cells accompanying these neurons undergo concomitant alterations that aggravate the course of neurodegeneration. As a result, these changes to neuroglial cells are now included in all the “pathogenic cascades” described in AD. Accordingly, astrogliosis and microgliosis, the main components of neuroinflammation, have been integrated into all the pathogenic theories of this disease, as discussed in this part of the two-part monograph that follows an accompanying article on gliopathogenesis and glioprotection. This initial reflection verified the implication of alterations to the neuroglia in AD, suggesting that these cells may also represent therapeutic targets to prevent neurodegeneration. In this second part of the monograph, we will analyze the possibilities of acting on glial cells to prevent or treat the neurodegeneration that is the hallmark of AD and other pathologies. Evidence of the potential of different pharmacological, non-pharmacological, cell and gene therapies (widely treated) to prevent or treat this disease is now forthcoming, in most cases as adjuncts to other therapies. A comprehensive AD multimodal therapy is proposed in which neuronal and neuroglial pharmacological treatments are jointly considered, as well as the use of new cell and gene therapies and non-pharmacological therapies that tend to slow down the progress of dementia.

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Drainage of senescent astrocytes from brain via meningeal lymphatic routes

Cited by 29 publications

References 78 publications

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

The Role of Glymphatic System in Alzheimer’s and Parkinson’s Disease Pathogenesis

Neuroimmune signaling at the brain borders

The relationships between neuroglial and neuronal changes in Alzheimer’s disease, and the related controversies II: gliotherapies and multimodal therapy

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