Glymphatic failure as a final common pathway to dementia

Science, Journal Year: 2020, Volume and Issue: 370(6512), P. 50 - 56

Published: Oct. 2, 2020

Sleep is evolutionarily conserved across all species, and impaired sleep a common trait of the diseased brain. quality decreases as we age, disruption regular architecture frequent antecedent to onset dementia in neurodegenerative diseases. The glymphatic system, which clears brain protein waste products, mostly active during sleep. Yet system degrades with suggesting causal relationship between disturbance symptomatic progression dementias. ties that bind sleep, aging, clearance, aggregation have shed new light on pathogenesis broad range diseases, for failure may constitute therapeutically targetable final pathway.

Language: Английский

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Fluid transport in the brain

Physiological Reviews, Journal Year: 2021, Volume and Issue: 102(2), P. 1025 - 1151

Published: May 5, 2021

The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. blood-brain barrier establishes stable environment that optimal for neuronal function, yet imposes physiological problem; transcapillary filtration forms extracellular fluid in other organs reduced to minimum brain. Consequently, depends on special [the cerebrospinal (CSF)] flushed into along perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined term glymphatic system, based dependency endfeet their adluminal expression of aquaporin-4 water channels facing CSF-filled spaces. Glymphatic clearance potentially harmful metabolic or protein waste products, such as amyloid-β, primarily active sleep, when drivers, cardiac cycle, respiration, slow vasomotion, together efficiently propel CSF inflow periarterial brain's space contains an abundance proteoglycans hyaluronan, which provide low-resistance hydraulic conduit rapidly can expand shrink sleep-wake cycle. system brain, meets requisites maintain homeostasis similar peripheral organs, considering blood-brain-barrier paths formation egress CSF.

Language: Английский

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The Glymphatic System: A Novel Component of Fundamental Neurobiology

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(37), P. 7698 - 7711

Published: Sept. 15, 2021

Throughout the body, lymphatic fluid movement supports critical functions including clearance of excess and metabolic waste. The glymphatic system is analog in CNS. As such, plays a key role regulating directional interstitial movement, waste clearance, and, potentially, brain immunity. enables bulk CSF from subarachnoid space along periarterial spaces, where it mixes with within parenchyma before ultimately exiting via perivenous spaces. This review focuses on important questions about structure this system, why needs transport unexplored aspects transport. We provide evidence that astrocytes blood vessels determine shape perivascular space, controlling fluid. Glymphatic has potential to alter local as well global signaling molecules metabolites. also highlight for cross talk among cardiovascular gastrointestinal tract, system. Much remains be studied, but we propose glymphatic/lymphatic acts cornerstone between body.

Language: Английский

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The glymphatic system: Current understanding and modeling

iScience, Journal Year: 2022, Volume and Issue: 25(9), P. 104987 - 104987

Published: Aug. 20, 2022

We review theoretical and numerical models of the glymphatic system, which circulates cerebrospinal fluid interstitial around brain, facilitating solute transport. Models enable hypothesis development predictions transport, with clinical applications including drug delivery, stroke, cardiac arrest, neurodegenerative disorders like Alzheimer's disease. sort existing into broad categories by anatomical function: Perivascular flow, transport in brain parenchyma, interfaces to perivascular spaces, efflux routes, links neuronal activity. Needs opportunities for future work are highlighted wherever possible; new models, expanded novel experiments inform could all have tremendous value advancing field.

Language: Английский

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The glymphatic hypothesis: the theory and the evidence

Fluids and Barriers of the CNS, Journal Year: 2022, Volume and Issue: 19(1)

Published: Feb. 3, 2022

Abstract The glymphatic hypothesis proposes a mechanism for extravascular transport into and out of the brain hydrophilic solutes unable to cross blood–brain barrier. It suggests that there is circulation fluid carrying inwards via periarterial routes, through interstitium outwards perivenous routes. This review critically analyses evidence surrounding mechanisms involved in each these stages. There good both influx efflux occur along routes but no principal route outflow perivenous. Furthermore, inflow unlikely be adequate provide would needed account solute efflux. A tenet flow sweeps parenchyma. However, velocity any possible circulatory within too small compared diffusion effective movement. By comparison earlier classical describing proposed entry parenchyma across barrier, movements by diffusion, partly near surfaces carried “preferred routes” including perivascular spaces, white matter tracts subependymal spaces. did not suggest Evidence still incomplete concerning fate leaving brain. large proportion eliminated from go lymph nodes before reaching blood proportions delivered directly or indirectly CSF which then enters are as yet unclear. In addition, understood why how absence AQP4 normally highly expressed on glial endfeet lining reduces rates elimination delivery it remote sites injection. Neither nor adequately explain move into, Features more complete description discussed. All aspects require further study.

Language: Английский

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A mesothelium divides the subarachnoid space into functional compartments

Science, Journal Year: 2023, Volume and Issue: 379(6627), P. 84 - 88

Published: Jan. 5, 2023

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes subarachnoid space in mouse human brain, designated lymphatic-like membrane (SLYM). SLYM morpho- immunophenotypically similar to mesothelial lining peripheral organs body cavities, it encases blood vessels harbors immune cells. Functionally, close apposition with endothelial venous sinus permits direct exchange small solutes between cerebrospinal fluid blood, thus representing equivalent arachnoid granulations. functional characterization provides fundamental insights into brain barriers transport.

Language: Английский

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Neuropathobiology of COVID-19: The Role for Glia

Frontiers in Cellular Neuroscience, Journal Year: 2020, Volume and Issue: 14

Published: Nov. 11, 2020

SARS-CoV-2, which causes the Coronavirus Disease 2019 (COVID-19) pandemic, has a strong brain neurotropism via binding to receptor angiotensin-converting enzyme 2 expressed by neurones and glial cells, including astrocytes microglia. Systemic infection accompanies severe cases of COVID-19 also triggers substantial increase in circulating levels chemokines interleukins that compromise blood-brain barrier, enter parenchyma affect its defensive systems, Brain areas devoid barrier such as circumventricular organs are particularly vulnerable inflammatory mediators. The performance microglia, well immune cells required for health, is considered critical defining neurological damage outcome COVID-19. In this review, we discuss implication neuroinflammation, adaptive innate immunity, autoimmunity, astrocytic microglial homeostatic functions psychiatric aspects consequences SARS-CoV-2 during ageing, presence systemic comorbidities, exposed pregnant mother foetus will be specifically covered.

Language: Английский

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Hypertension, Neurovascular Dysfunction, and Cognitive Impairment

Hypertension, Journal Year: 2022, Volume and Issue: 80(1), P. 22 - 34

Published: Oct. 5, 2022

Hypertension affects a significant proportion of the adult and aging population represents an important risk factor for vascular cognitive impairment late-life dementia. Chronic high blood pressure continuously challenges structural functional integrity cerebral vasculature, leading to microvascular rarefaction dysfunction, neurovascular uncoupling that typically impairs supply. disrupts blood-brain barrier integrity, promotes neuroinflammation, may contribute amyloid deposition Alzheimer pathology. The mechanisms underlying these harmful effects are still focus investigation, but studies in animal models have provided molecular cellular mechanistic insights. Remaining questions relate whether adequate treatment hypertension prevent deterioration function, threshold treatment, most effective antihypertensive drugs. Recent advances biology, advanced brain imaging, detection subtle behavioral phenotypes begun provide insights into critical issues. Importantly, parallel analysis parameters humans is feasible, making it possible foster translational advancements. In this review, we evaluation evidence available experimental examine progress made identify remaining gaps knowledge.

Language: Английский

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The Glymphatic System (En)during Inflammation

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7491 - 7491

Published: July 13, 2021

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

Language: Английский

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Cerebrospinal fluid can exit into the skull bone marrow and instruct cranial hematopoiesis in mice with bacterial meningitis

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(5), P. 567 - 576

Published: May 1, 2022

Language: Английский

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