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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Selective removal of astrocytic APOE4 strongly protects against tau-mediated neurodegeneration and decreases synaptic phagocytosis by microglia

Neuron, Journal Year: 2021, Volume and Issue: 109(10), P. 1657 - 1674.e7

Published: April 7, 2021

Language: Английский

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Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis

Brain, Journal Year: 2021, Volume and Issue: 145(1), P. 64 - 75

Published: Sept. 8, 2021

Abstract Aquaporin channels facilitate bidirectional water flow in all cells and tissues. AQP4 is highly expressed astrocytes. In the CNS, it enriched astrocyte endfeet, at synapses, glia limitans, where mediates exchange across blood–spinal cord blood–brain barriers (BSCB/BBB), controls cell volume, extracellular space migration. Perivascular enrichment of BSCB/BBB suggests a role glymphatic function. Recently, we have demonstrated that localization also dynamically regulated subcellular level, affecting membrane permeability. Ageing, cerebrovascular disease, traumatic CNS injury, sleep disruption are established emerging risk factors developing neurodegeneration, animal models each, impairment function associated with changes perivascular localization. oedema caused by passive influx through response to osmotic imbalances. We reducing dynamic relocalization reduces accelerates functional recovery rodent models. Given difficulties pore-blocking inhibitors, targeting opens up new treatment avenues for oedema, neurovascular neurodegenerative diseases, provides framework address fundamental questions about homeostasis health disease.

Language: Английский

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Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 219(3)

Published: Feb. 25, 2022

Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but also actively released into the extracellular fluids including brain interstitial fluid and cerebrospinal (CSF). However, it remains elusive whether clearance impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), major driver glymphatic system, facilitates elimination from to CSF subsequently deep cervical lymph nodes. Strikingly, deletion AQP4 not only elevated markedly exacerbated phosphorylated deposition associated neurodegeneration brains transgenic mice expressing P301S mutant tau. The current study identified pathway central nervous suggesting novel regulatory mechanism whose impairment contributes aggregation

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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Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation?

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 16, 2022

As inflammation in the brain contributes to several neurological and psychiatric diseases, cause of neuroinflammation is being widely studied. The causes can be roughly divided into following domains: viral infection, autoimmune disease, from peripheral organs, mental stress, metabolic disorders, lifestyle. In particular, effects caused by organs have yet unclear mechanisms. Many such as gastrointestinal inflammation, chronic obstructive pulmonary rheumatoid arthritis, dermatitis, fatigue syndrome, or myalgic encephalomyelitis (CFS/ME), trigger through pathways. mechanisms action for inflammation-induced include disruption blood-brain barrier, activation glial cells associated with systemic immune activation, on autonomic nerves via organ-brain axis. this review, we consider previous studies relationship between neuroinflammation, focusing regions susceptible inflammation.

Language: Английский

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Glymphatic system impairment in multiple sclerosis: relation with brain damage and disability

Brain, Journal Year: 2021, Volume and Issue: 145(8), P. 2785 - 2795

Published: Dec. 13, 2021

Recent evidence has shown the existence of a CNS 'waste clearance' system, defined as glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer's and Parkinson's disease. function not thoroughly explored multiple sclerosis, where processes are intermingled with inflammatory processes. We aimed to investigate system sclerosis evaluate its association clinical disability, disease course, demyelination neurodegeneration, quantified using different MRI techniques. In this retrospective study, we enrolled 71 patients (49 relapsing-remitting 22 progressive sclerosis) 32 age- sex-matched healthy control subjects. All subjects underwent neurological assessment high-resolution T1, T2 double inversion recovery sequences, diffusion susceptibility weighted imaging. calculated along perivascular space index, proxy for function, cortical deep grey matter volume, white lesion volume normal-appearing microstructural damage. Multiple showed an overall lower index versus controls (estimated mean difference: -0.09, P = 0.01). Both had -0.06, 0.04 -0.19, 0.001 patients). Progressive 0.03). patients, was associated more severe disability (r -0.45, 0.001) longer duration -0.37, 0.002). Interestingly, detected negative between first 4.13 years course -0.38, 0.04) without any thereafter (up 34 duration). Lower higher -0.36, 0.003) -0.41, 0.30, 0.007) 0.42, atrophy, reduced fractional anisotropy increased diffusivity matter. Our results suggest that is impaired especially stages. Impaired measures both neurodegeneration reflects disability. These findings impairment may be pathological mechanism underpinning sclerosis. The dynamic interplay other substrates deserves further investigation.

Language: Английский

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Loss of perivascular aquaporin-4 localization impairs glymphatic exchange and promotes amyloid β plaque formation in mice

Alzheimer s Research & Therapy, Journal Year: 2022, Volume and Issue: 14(1)

Published: April 26, 2022

Abstract Background Slowed clearance of amyloid β (Aβ) is believed to underlie the development Aβ plaques that characterize Alzheimer’s disease (AD). cleared in part by glymphatic system, a brain-wide network perivascular pathways supports exchange cerebrospinal and brain interstitial fluid. Glymphatic clearance, or CSF-interstitial fluid exchange, dependent on astroglial water channel aquaporin-4 (AQP4) as deletion Aqp4 mice slows impairs promotes plaque formation. Methods To define role AQP4 human AD, we evaluated expression localization post mortem case series. We then used α-syntrophin ( Snta1 ) knockout mouse model which lacks evaluate effect loss has CSF tracer distribution. Lastly, crossed this line into amyloidosis (Tg2576 mice) levels. Results In series, observed reduced frontal cortical gray matter subjects with AD compared cognitively intact subjects. This decline was associated increasing neurofibrillary pathological burden, cognitive prior dementia onset. rodent studies, gene slowed influx efflux from increased Conclusions These findings suggest may contribute pathology populations.

Language: Английский

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The glymphatic system: implications for drugs for central nervous system diseases

Nature Reviews Drug Discovery, Journal Year: 2022, Volume and Issue: 21(10), P. 763 - 779

Published: Aug. 10, 2022

Language: Английский

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