The glymphatic hypothesis: the theory and the evidence DOI Creative Commons
Stephen B. Hladky,

Margery A. Barrand

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

Glymphatic failure as a final common pathway to dementia DOI

Maiken Nedergaard,

Steven A. Goldman

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

Citations

661
Cerebral amyloid angiopathy and Alzheimer disease — one peptide, two pathways DOI
Steven M. Greenberg, Brian J. Bacskai, Mar Hernández‐Guillamón

et al.

Nature Reviews Neurology, Journal Year: 2019, Volume and Issue: 16(1), P. 30 - 42

Published: Dec. 11, 2019

Language: Английский

Citations

634
Perivascular spaces in the brain: anatomy, physiology and pathology DOI
Joanna M. Wardlaw, Helene Benveniste,

Maiken Nedergaard

et al.

Nature Reviews Neurology, Journal Year: 2020, Volume and Issue: 16(3), P. 137 - 153

Published: Feb. 24, 2020

Language: Английский

Citations

613
History and progress of hypotheses and clinical trials for Alzheimer’s disease DOI Creative Commons
Peipei Liu, Yi Xie, Xiao‐Yan Meng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2019, Volume and Issue: 4(1)

Published: Aug. 23, 2019

Abstract Alzheimer’s disease (AD) is a neurodegenerative characterized by progressive memory loss along with neuropsychiatric symptoms and decline in activities of daily life. Its main pathological features are cerebral atrophy, amyloid plaques, neurofibrillary tangles the brains patients. There various descriptive hypotheses regarding causes AD, including cholinergic hypothesis, tau propagation mitochondrial cascade calcium homeostasis neurovascular inflammatory metal ion lymphatic system hypothesis. However, ultimate etiology AD remains obscure. In this review, we discuss related clinical trials. Wealthy puzzles lessons have made it possible to develop explanatory theories identify potential strategies for therapeutic interventions AD. The combination hypometabolism autophagy deficiency likely be causative factor We further propose that fluoxetine, selective serotonin reuptake inhibitor, has treat

Language: Английский

Citations

577
The blood–brain barrier in health and disease: Important unanswered questions DOI Creative Commons
Caterina P. Profaci, Roeben N. Munji,

Robert S. Pulido

et al.

The Journal of Experimental Medicine, Journal Year: 2020, Volume and Issue: 217(4)

Published: March 25, 2020

The blood vessels vascularizing the central nervous system exhibit a series of distinct properties that tightly control movement ions, molecules, and cells between parenchyma. This “blood–brain barrier” is initiated during angiogenesis via signals from surrounding neural environment, its integrity remains vital for homeostasis protection throughout life. Blood–brain barrier dysfunction contributes to pathology in range neurological conditions including multiple sclerosis, stroke, epilepsy, has also been implicated neurodegenerative diseases such as Alzheimer’s disease. review will discuss current knowledge key unanswered questions regarding blood–brain health

Language: Английский

Citations

564
Circadian control of brain glymphatic and lymphatic fluid flow DOI Creative Commons
Lauren M. Hablitz, Virginia Plá, Michael Giannetto

et al.

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 2, 2020

The glymphatic system is a network of perivascular spaces that promotes movement cerebrospinal fluid (CSF) into the brain and clearance metabolic waste. This transport supported by water channel aquaporin-4 (AQP4) localized to vascular endfeet astrocytes. more effective during sleep, but whether sleep timing function remains unknown. We here show influx exhibit endogenous, circadian rhythms peaking mid-rest phase mice. Drainage CSF from cisterna magna lymph nodes exhibits daily variation opposite influx, suggesting distribution throughout animal depends on time-of-day. polarization AQP4 highest rest loss eliminates day-night difference in both drainage nodes. conclude under control supports this rhythm.

Language: Английский

Citations

443
Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia DOI Creative Commons
Lauren M. Hablitz, Hanna S. Vinitsky, Qian Sun

et al.

Science Advances, Journal Year: 2019, Volume and Issue: 5(2)

Published: Feb. 1, 2019

We show that glymphatic influx into the brain occurs in direct proportion to slow cortical activity and inversely heart rate.

Language: Английский

Citations

436
The Brain’s Glymphatic System: Current Controversies DOI Creative Commons
Humberto Mestre, Yuki Mori, Maiken Nedergaard

et al.

Trends in Neurosciences, Journal Year: 2020, Volume and Issue: 43(7), P. 458 - 466

Published: May 15, 2020

The glymphatic concept along with the discovery of meningeal lymphatic vessels have, in recent years, highlighted that fluid is directionally transported within central nervous system (CNS). Imaging studies, as well manipulations transport, point to a key role glymphatic-lymphatic clearance amyloid-β and other proteins. As such, represents new target combating neurodegenerative diseases. Not unexpectedly, introduction plumbing brain has stirred controversies. This opinion article will highlight what we know about brain's transport systems, where experimental data are lacking, still debated.

Language: Английский

Citations

435
The Glymphatic System and Waste Clearance with Brain Aging: A Review DOI
Helene Benveniste, Xiaodan Liu, Sunil Koundal

et al.

Gerontology, Journal Year: 2018, Volume and Issue: 65(2), P. 106 - 119

Published: July 11, 2018

The glymphatic system is a glial-dependent waste clearance pathway in the brain, place of lymphatic vessels, dedicated to drain away soluble proteins and metabolic products. Specifically, network serves as “front end” for clearance, connected downstream an authentic network, associated with dura covering brain well cranial nerves large vessels at skull exits. anatomical functional interconnections between these two networks are not completely understood. Several key physiological processes have been identified that control transport function from brain. In this review, we aim provide overview discussion concept behind system, current evidence, controversies, while specifically focusing on consequences aging evidence its existence human Discovering novel strategies optimizing maintaining efficient across lifespan may future prove be important preventing cognitive decline sustaining healthy aging.

Language: Английский

Citations

393
Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model DOI Creative Commons
Ian F. Harrison, Ozama Ismail, Asif Machhada

et al.

Brain, Journal Year: 2020, Volume and Issue: 143(8), P. 2576 - 2593

Published: May 14, 2020

Abstract The glymphatic system, that is aquaporin 4 (AQP4) facilitated exchange of CSF with interstitial fluid (ISF), may provide a clearance pathway for protein species such as amyloid-β and tau, which accumulate in the brain Alzheimer’s disease. Further, tau transference via extracellular space, compartment cleared by pathway, allows its neuron-to-neuron propagation, regional progression tauopathy disorder. system therefore represents an exciting new target Here we aim to understand involvement CSF-ISF pathology. First, demonstrate impaired AQP4 polarization mouse model tauopathy, suggesting this have potential exacerbate or even induce pathogenic accumulation tau. Subsequently, establish central role from brain; showing marked using novel inhibitor, TGN-020. As such, show presents druggable treatment disease, possibly other neurodegenerative diseases alike.

Language: Английский

Citations

393