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      The glymphatic system: Current understanding and modeling

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

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          Neuroscience; Neuroanatomy; Systems biology

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          Most cited references254

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          The amyloid hypothesis of Alzheimer's disease at 25 years

          Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
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            A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β.

            Because it lacks a lymphatic circulation, the brain must clear extracellular proteins by an alternative mechanism. The cerebrospinal fluid (CSF) functions as a sink for brain extracellular solutes, but it is not clear how solutes from the brain interstitium move from the parenchyma to the CSF. We demonstrate that a substantial portion of subarachnoid CSF cycles through the brain interstitial space. On the basis of in vivo two-photon imaging of small fluorescent tracers, we showed that CSF enters the parenchyma along paravascular spaces that surround penetrating arteries and that brain interstitial fluid is cleared along paravenous drainage pathways. Animals lacking the water channel aquaporin-4 (AQP4) in astrocytes exhibit slowed CSF influx through this system and a ~70% reduction in interstitial solute clearance, suggesting that the bulk fluid flow between these anatomical influx and efflux routes is supported by astrocytic water transport. Fluorescent-tagged amyloid β, a peptide thought to be pathogenic in Alzheimer's disease, was transported along this route, and deletion of the Aqp4 gene suppressed the clearance of soluble amyloid β, suggesting that this pathway may remove amyloid β from the central nervous system. Clearance through paravenous flow may also regulate extracellular levels of proteins involved with neurodegenerative conditions, its impairment perhaps contributing to the mis-accumulation of soluble proteins.
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              Sleep drives metabolite clearance from the adult brain.

              The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
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                Author and article information

                Contributors
                Journal
                iScience
                iScience
                iScience
                Elsevier
                2589-0042
                20 August 2022
                16 September 2022
                20 August 2022
                : 25
                : 9
                : 104987
                Affiliations
                [1 ]Department of Physics, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
                [2 ]Department of Applied Mathematics and Computer Science, Technical University of Denmark, Richard Petersens Plads, 2800 Kgs. Lyngby, Denmark
                [3 ]Neuroscience and Rare Diseases Discovery and Translational Area, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070 Basel, Switzerland
                [4 ]Department of Cell Biology and The Robert Furchgott Center for Neural and Behavioral Science, State University of New York Downstate Medical Center, Brooklyn, NY, USA
                [5 ]Oulu Functional NeuroImaging, Department of Diagnostic Radiology, MRC, Oulu University Hospital, Oulu, Finland
                [6 ]Medical Imaging, Physics and Technology, the Faculty of Medicine, University of Oulu, Oulu, Finland
                [7 ]Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
                [8 ]Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
                [9 ]Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [10 ]Department of Emergency Medicine and Services, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
                [11 ]Department of Experimental Medical Science, Lund University, Lund, Sweden
                [12 ]Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden
                [13 ]Department of Mathematics, University of Oslo, Oslo, Norway
                [14 ]Simula Research Laboratory, Department of Numerical Analysis and Scientific Computing, Oslo, Norway
                [15 ]Centre for Mathematical Sciences, Lund University, Sweden
                [16 ]Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [17 ]Instítut Interdisciplinaire de Neurosciences, Université de Bordeaux / CNRS UMR 5297, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, CS 61292 Case 130, 33076 Bordeaux Cedex France
                [18 ]Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USA
                [19 ]Department of Cell Biology, SUNY Downstate Health Sciences University, Brooklyn, NY, USA
                [20 ]Departments of Computer Science/ Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA
                [21 ]Department of Mechanical Engineering, University of Rochester, Rochester, 14627 NY, USA
                [22 ]Department of Mechanical Engineering, University of Minnesota, Minneapolis, USA
                [23 ]Department of Anesthesiology, Yale School of Medicine, New Haven, CT, USA
                [24 ]Department of Biomedical Engineering, Yale School of Medicine, New Haven, CT, USA
                [25 ]VISN 20 Mental Illness Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA
                [26 ]Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA
                [27 ]Department of Neurology, University of Washington School of Medicine, Seattle, WA, USA
                [28 ]Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
                [29 ]Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, 14642 NY, USA
                Author notes
                []Corresponding author d.h.kelley@ 123456rochester.edu
                [∗∗ ]Corresponding author maiken_nedergaard@ 123456urmc.rochester.edu
                [30]

                Lead contact

                Article
                S2589-0042(22)01259-7 104987
                10.1016/j.isci.2022.104987
                9460186
                36093063
                d6a54623-ffa2-4fba-a099-4c720061a5b1
                © 2022 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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                neuroscience,neuroanatomy,systems biology
                neuroscience, neuroanatomy, systems biology

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