The Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future

Annual Review of Pathology Mechanisms of Disease, Год журнала: 2017, Номер 13(1), С. 379 - 394

Опубликована: Дек. 1, 2017

The central nervous system (CNS) is unique in being the only organ lacking lymphatic vessels to assist removal of interstitial metabolic waste products. Recent work has led discovery glymphatic system, a glial-dependent perivascular network that subserves pseudolymphatic function brain. Within pathway, cerebrospinal fluid (CSF) enters brain via periarterial spaces, passes into interstitium astrocytic aquaporin-4, and then drives perivenous drainage (ISF) its solute. Here, we review role pathway CNS physiology, factors known regulate flow, pathologic processes which breakdown CSF-ISF exchange been implicated disease initiation progression. Important areas future research, including manipulation activity aiming improve clearance therapeutic agent delivery, are also discussed.

Язык: Английский

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Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence

Fluids and Barriers of the CNS, Год журнала: 2014, Номер 11(1), С. 26 - 26

Опубликована: Янв. 1, 2014

Interstitial fluid (ISF) surrounds the parenchymal cells of brain and spinal cord while cerebrospinal (CSF) fills larger spaces within around CNS. Regulation composition volume these fluids is important for effective functioning achieved by barriers that prevent free exchange between CNS blood mechanisms secrete controlled into distribute reabsorb it. Structures associated with this regular turnover include choroid plexuses, capillaries comprising blood-brain barrier, arachnoid villi perineural penetrating cribriform plate. ISF flow, estimated from rates removal markers brain, has been thought to reflect secretion across although questioned because measurements were made under barbiturate anaesthesia possibly affecting flow CSF influx parenchyma via perivascular routes may deliver independently barrier secretion. Fluid at provided specific transporters generate solute fluxes so creating osmotic gradients force water follow. Any due hydrostatic pressures driving soon ceases unless accompanied transport movements modify concentrations. be derived primarily plexuses. Flow measured using phase contrast magnetic resonance imaging reveal more rapid variable than previously supposed, even implying some circumstances net through cerebral aqueduct reversed third lateral ventricles. Such requires there alternative sites both generation CSF. Fluorescent tracer analysis shown can occur along periarterial spaces. Whether represents whether subsequent interstitium out cortex perivenous routes, described as glymphatic circulation, remains established. Modern techniques have revealed complex brain. This review provides a critical evaluation data.

Язык: Английский

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Understanding the functions and relationships of the glymphatic system and meningeal lymphatics

Journal of Clinical Investigation, Год журнала: 2017, Номер 127(9), С. 3210 - 3219

Опубликована: Авг. 31, 2017

Recent discoveries of the glymphatic system and meningeal lymphatic vessels have generated a lot excitement, along with some degree skepticism. Here, we summarize state field point out gaps knowledge that should be filled through further research. We discuss as allows CNS perfusion by cerebrospinal fluid (CSF) interstitial (ISF). also describe recently characterized their role in drainage brain ISF, CSF, CNS-derived molecules, immune cells from meninges to peripheral (CNS-draining) lymph nodes. speculate on relationship between two systems malfunction may underlie neurological diseases. Although much remains investigated, these new changed our understanding mechanisms underlying privilege drainage. Future studies explore communications lymphatics disorders develop therapeutic modalities targeting systems.

Язык: Английский

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Aquaporin-4-dependent glymphatic solute transport in the rodent brain

eLife, Год журнала: 2018, Номер 7

Опубликована: Дек. 18, 2018

The glymphatic system is a brain-wide clearance pathway; its impairment contributes to the accumulation of amyloid-β. Influx cerebrospinal fluid (CSF) depends upon expression and perivascular localization astroglial water channel aquaporin-4 (AQP4). Prompted by recent failure find an effect Aqp4 knock-out (KO) on CSF interstitial (ISF) tracer transport, five groups re-examined importance AQP4 in transport. We concur that influx higher wild-type mice than four different KO lines one line lacks (Snta1 KO). Meta-analysis all studies demonstrated significant decrease transport rats compared controls. Meta-regression indicated anesthesia, age, delivery explain opposing results. also report intrastriatal injections suppress function. This validates role shows must avoid use invasive procedures.

Язык: Английский

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The role of brain barriers in fluid movement in the CNS: is there a ‘glymphatic’ system?

Acta Neuropathologica, Год журнала: 2018, Номер 135(3), С. 387 - 407

Опубликована: Фев. 10, 2018

Brain fluids are rigidly regulated to provide stable environments for neuronal function, e.g., low K+, Ca2+, and protein optimise signalling minimise neurotoxicity. At the same time, astroglial waste must be promptly removed. The interstitial fluid (ISF) of brain tissue cerebrospinal (CSF) bathing CNS integral this homeostasis idea a glia-lymph or 'glymphatic' system clearance from has developed over last 5 years. This links bulk (convective) flow CSF into along outside penetrating arteries, glia-mediated convective transport solutes through extracellular space (ECS) involving aquaporin-4 (AQP4) water channel, finally delivery venules peri-venous spaces. However, recent evidence favours important amendments hypothesis, particularly concerning role glia transfer within ECS. review discusses studies which question AQP4 in ISF lack its ability solutes; summarizes attributes ECS that strongly favour diffusion small large molecules without flow; work on hydraulic conductivity nature matrix may impede movement; reconsiders roles perivascular (PVS) CSF-ISF exchange drainage. We also consider extent is possible desirable, impact neuropathology drainage, why using as proxy measure components drug problematic. propose new key historical both support concept system, whereby enters via PVS dispersion larger caliber arteries/arterioles, predominantly regulates CSF/ISF at level neurovascular unit associated with microvessels, and, finally, mixture CSF/ISF/waste products normally cleared venules/veins well other pathways; such not constitute true 'circulation', but, least, suggests comprehensive re-evaluation previously proposed concepts better taking account basic cerebrovascular physiology considerations.

Язык: Английский

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Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease

Neurobiology of Disease, Год журнала: 2016, Номер 93, С. 215 - 225

Опубликована: Май 25, 2016

Язык: Английский

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Emerging concepts in sporadic cerebral amyloid angiopathy

Brain, Год журнала: 2017, Номер 140(7), С. 1829 - 1850

Опубликована: Фев. 27, 2017

Sporadic cerebral amyloid angiopathy is a common, well-defined small vessel disease and largely untreatable cause of intracerebral haemorrhage contributor to age-related cognitive decline. The term 'cerebral angiopathy' now encompasses not only specific cerebrovascular pathological finding, but also different clinical syndromes (both acute progressive), brain parenchymal lesions seen on neuroimaging set diagnostic criteria—the Boston criteria, which have resulted in increasingly detected during life. Over the past few years, it has become clear that, at pathophysiological level, appears be part protein elimination failure that this dysfunction feed-forward process, potentially leads worsening vascular amyloid-β accumulation, activation injury pathways impaired physiology. From standpoint, characterized by individual focal (microbleeds, cortical superficial siderosis, microinfarcts) large-scale alterations (white matter hyperintensities, structural connectivity, thickness), both subcortical. This review provides an interdisciplinary critical outlook various emerging changing concepts field, illustrating mechanisms associated with pathology neurological dysfunction.

Язык: Английский

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Bidirectional relationship between sleep and Alzheimer’s disease: role of amyloid, tau, and other factors

Neuropsychopharmacology, Год журнала: 2019, Номер 45(1), С. 104 - 120

Опубликована: Авг. 13, 2019

Язык: Английский

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Astrocytes in chronic pain and itch

Nature reviews. Neuroscience, Год журнала: 2019, Номер 20(11), С. 667 - 685

Опубликована: Сен. 19, 2019

Язык: Английский

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Neurovascular and Cognitive Dysfunction in Hypertension

Circulation Research, Год журнала: 2019, Номер 124(7), С. 1025 - 1044

Опубликована: Март 28, 2019

Hypertension has emerged as a leading cause of age-related cognitive impairment. Long known to be associated with dementia caused by vascular factors, hypertension more recently been linked also Alzheimer disease-the major in older people. Thus, although midlife is risk factor for late-life dementia, may promote the neurodegenerative pathology underlying disease. The mechanistic bases these harmful effects remain established. well alter structure and function cerebral blood vessels, but how cerebrovascular lead impairment disease not understood. Furthermore, critical questions concern whether treatment prevents impairment, pressure threshold treatment, antihypertensive agents used. Recent advances neurovascular biology, epidemiology, brain imaging, biomarker development have started provide new insights into issues. In this review, we will examine progress made date, and, after evaluation evidence, highlight still outstanding seek path forward future studies.

Язык: Английский

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