Impairment of paravascular clearance pathways in the aging brain
Open accessAbstract
Objective: In the brain, protein waste removal is partly performed by paravascular pathways that facilitate convective exchange of water and soluble contents between cerebrospinal fluid (CSF) and interstitial fluid (ISF). Several lines of evidence suggest that bulk flow drainage via the glymphatic system is driven by cerebrovascular pulsation, and is dependent on astroglial water channels that line paravascular CSF pathways. The objective of this study was to evaluate whether the efficiency of CSF–ISF exchange and interstitial solute clearance is impaired in the aging brain. Methods: CSF–ISF exchange was evaluated by in vivo and ex vivo fluorescence microscopy and interstitial solute clearance was evaluated by radiotracer clearance assays in young (2–3 months), middle‐aged (10–12 months), and old (18–20 months) wild‐type mice. The relationship between age‐related changes in the expression of the astrocytic water channel aquaporin‐4 (AQP4) and changes in glymphatic pathway function was evaluated by immunofluorescence. Results: Advancing age was associated with a dramatic decline in the efficiency of exchange between the subarachnoid CSF and the brain parenchyma. Relative to the young, clearance of intraparenchymally injected amyloid‐β was impaired by 40% in the old mice. A 27% reduction in the vessel wall pulsatility of intracortical arterioles and widespread loss of perivascular AQP4 polarization along the penetrating arteries accompanied the decline in CSF–ISF exchange. Interpretation: We propose that impaired glymphatic clearance contributes to cognitive decline among the elderly and may represent a novel therapeutic target for the treatment of neurodegenerative diseases associated with accumulation of misfolded protein aggregates. Ann Neurol 2014;76:845–861
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In Alzheimer's disease, reactive astrogliosis is upregulated, corresponds to the severity of astroglial activation and high levels of proinflammatory cytokines, and hypertrophic processes make aberrant contacts with nearby cerebral vessels and neurons, leading to neurovascular uncoupling.
“In AD, reactive astrogliosis is upregulated corresponds to the severity of astroglial activation and high levels of proinflammatory cytokines and the hypertrophic processes make aberrant contacts with nearby cerebral vessels and neurons, leading to neurovascular uncoupling.[ 42 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [42]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredImpaired glymphatic function has been suggested to be instrumental in a range of brain diseases, including Alzheimer's dementia, posttraumatic encephalopathy, ageing, sleep, depression, and exercise.
“Impaired glymphatic function has been suggested to be instrumental in a range of brain diseases; this has been illustrated most in Alzheimer's dementia (7, 19, 20) but has also been shown to be relevant in posttraumatic encephalopathy (21), ageing (22), sleep (23, 24), depression (20), and exercise (25).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [22]
Paravascular clearance has been shown to be impaired with ageing.
“and paravascular clearance has been shown to be impaired with ageing (22).”
From Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. (2018) · cites this paper as [22]
The glymphatic system degrades with age.
“Yet the glymphatic system degrades with age, suggesting a causal relationship between sleep disturbance and symptomatic progression in the neurodegenerative dementias.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
Aging is associated with a steep fall in glymphatic flow in rodent and human brains.
“Aging is also associated with a steep fall in glymphatic flow in the brains of both rodents and humans.”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
CSF inflow of larger tracers is reduced by up to 85% in aged wild-type mice.
“CSF inflow of larger tracers are reduced by up to 85% in aged wild-type mice”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
The decrease in glymphatic flow in old mice is partly mediated by mislocation of AQP4 away from the vascular wall and possibly by atrophy of meningeal lymphatic vessels.
“The decrease in glymphatic flow in old mice is in part mediated by mislocation of AQP4 water channels away from the vascular wall (52) and possible by atrophy of meningeal lymphatic vessel (42).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
Contrast clearance in human brain tissue is inversely correlated with age in all subjects studied.
“while contrast clearance in human brain tissue was inversely correlated to age in all subjects studied (50, 52–54).”
From Glymphatic failure as a final common pathway to dementia (2020) · cites this paper as [52]
As individuals age, there is a decline in the efficiency of glymphatic transport mechanisms in eliminating waste products such as Aβ.
“As individuals age, there is a decline in the efficiency of these transport mechanisms in eliminating waste products such as Aβ.156,157”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [157]
Both the brain glymphatic and meningeal lymphatic systems deteriorate with age and their dysfunction can potentiate AD pathology and dementia.
“both the brain glymphatic and meningeal lymphatic systems deteriorate with age”
From Living on the Edge of the CNS: Meninges Cell Diversity in Health and Disease (2021) · cites this paper as Kress et al., 2014
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“Additionally, we have observed that at infusion rates that do not change ICP, paravascular CSF tracer flux follows the same patterns observed in the present study.(5,8) Because paravascular CSF recirculation occurs long after the normalization of ICP after the cessation of tracer infusion, the CSF tracer fluxes observ…”
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“Additionally, we have observed that at infusion rates that do not change ICP, paravascular CSF tracer flux follows the same patterns observed in the present study.(5,8) Because paravascular CSF recirculation occurs long after the normalization of ICP after the cessation of tracer infusion, the CSF tracer fluxes observ…”
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“Reactive astrogliosis, a feature of the aging brain,(34) is associated in several injury models with the loss of perivascular AQP4 polarization, as AQP4 distributes along nonperivascular fine astrocytic processes.(13,14) On the basis of these observations, we tested here whether the loss of AQP4 polarity contributes t…”
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“Impairment of glymphatic pathway function was accompanied by a 27% reduction in cerebral arterial wall pulsatility, which is an important contributor to paravascular flux along the glymphatic pathway.(7,17,26) In addition, we show that impairment of paravascular CSF–ISF exchange is similarly associated with loss of pe…”
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“Prior histopathological studies in both clinical AD cases and in transgenic models of AD have demonstrated that amyloid plaque deposition causes a loss of perivascular AQP4 polarization.(35,36) These and the present findings suggests that age-related changes in perivascular AQP4 polarization, impaired glymphatic clear…”
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“All experimental procedures were adapted from the previous studies.(6,12) The single-barrel iontophoresis microelectrode (tip FIGURE 1: Vascular pulsatility is suppressed in the penetrating arteries of the aging brain.”
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“In human cerebral arteries, vascular wall compliance is reduced as a function of age,(30) and a recent clinical study demonstrated that loss of peripheral vascular compliance is associated with increased Ab deposition in patients with mild cognitive impairment.(31) Loss of arterial wall compliance is the most facile e…”
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“Reactive astrogliosis, a feature of the aging brain,(34) is associated in several injury models with the loss of perivascular AQP4 polarization, as AQP4 distributes along nonperivascular fine astrocytic processes.(13,14) On the basis of these observations, we tested here whether the loss of AQP4 polarity contributes t…”
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“Here it is intriguing to note that peripheral inflammation likewise slows interstitial bulk flow and the clearance Ab from the brain.(38) Based upon these findings, it is possible that peripheral inflammation may impair glymphatic pathway function and may contribute to the present age-related decline in paravascular C…”
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“Prior histopathological studies in both clinical AD cases and in transgenic models of AD have demonstrated that amyloid plaque deposition causes a loss of perivascular AQP4 polarization.(35,36) These and the present findings suggests that age-related changes in perivascular AQP4 polarization, impaired glymphatic clear…”
BackgroundFluid mechanics in the perivascular space
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“However, over greater distances, such as the millimeter–centimeter scales that separate areas of the brain interstitium from distant CSF compartments, bulk flow must facilitate the clearance particularly of peptide- and protein-sized interstitial solutes.(39,40) One possibility is that a substantial proportion of inte…”
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“between age-related glymphatic dysfunction and amyloid pathologies.(248) These areas are attractive targets for future”
BackgroundThe Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade
Cline, E. N., Bicca, M. A., Viola, K. L., & Klein, W. L. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179941 · Cited by 870 · see citing works
“Recent studies in mice show that glymphatic activity decreases sharply during aging, resulting in decreased A clearance from the brain [320].”
BackgroundThe Glymphatic System in Central Nervous System Health and Disease: Past, Present, and Future
Plog, B. A., & Nedergaard, M. (2017) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-051217-111018 · Cited by 780 · see citing works
“It has been demonstrated that there is an age-associated decline in glymphatic CSF influx, as well as interstitial solute clearance, including Aβ, and this appears to be related to reduced penetrating arterial pulsatility in the aged brain (58).”
BackgroundMethodSelf-citationAquaporin-4-dependent glymphatic solute transport in the rodent brain
Mestre, H., Hablitz, L. M., Xavier, A. L., Feng, W., Zou, W., Pu, T., Monai, H., Murlidharan, G., Castellanos Rivera, R. M., Simon, M. J., et al. (2018) · eLife · doi:10.7554/elife.40070 · Cited by 738 · see citing works
“6 mm was conducted to identify which regions accounted for the differences in CSF influx (Kress et al., 2014).”
BackgroundMethodInfluentialSelf-citationThe blood-brain barrier in aging and neurodegeneration
Knox, E. G., Aburto, M. R., Clarke, G., Cryan, J. F., & O’Driscoll, C. M. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01511-z · Cited by 738 · see citing works
“Interestingly, systems regulating the circulation of brain extracellular fluid and cerebrospinal fluid, such as the glymphatic system, are also decreased with healthy aging [53, 100].”
BackgroundGlymphatic MRI in idiopathic normal pressure hydrocephalus
Ringstad, G., Vatnehol, S. A. S., & Eide, P. K. (2017) · Brain · doi:10.1093/brain/awx191 · Cited by 722 · see citing works
“It can therefore not be established to what degree iNPH disease or age/gender contributed to differences between groups, while reduced glymphatic function should be expected with normal ageing (Kress et al., 2014).”
BackgroundCircadian control of brain glymphatic and lymphatic fluid flow
Hablitz, L. M., Plá, V., Giannetto, M., Vinitsky, H. S., Stæger, F. F., Metcalfe, T., Nguyen, R., Benrais, A., & Nedergaard, M. (2020) · Nature Communications · doi:10.1038/s41467-020-18115-2 · Cited by 704 · see citing works
“In both a standard LD cycle (day: n= 7 mice; night n= 5 mice) and in 10 days LL (rest: n= 7 mice; active: n= 7 mice) we found no significant differences in contractions per minute between the rest and active phases (two-way analysis of variance (ANOVA), main effect of phase: F(1, 22)= 0.”
MethodSelf-citationThree dimensions of the amyloid hypothesis: time, space and 'wingmen'
Musiek, E. S., & Holtzman, D. M. (2015) · Nature Neuroscience · doi:10.1038/nn.4018 · Cited by 697 · see citing works
The Lymphatic Vasculature in the 21st Century: Novel Functional Roles in Homeostasis and Disease
Oliver, G. C., Kipnis, J., Randolph, G. J., & Harvey, N. L. (2020) · Cell · doi:10.1016/j.cell.2020.06.039 · Cited by 685 · see citing works
“Aging is also associated with impaired glymphatic flow (Kress et al., 2014).”
Revisiting the Mechanisms of CNS Immune Privilege
Louveau, A., Harris, T. H., & Kipnis, J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.08.006 · Cited by 682 · see citing works
Zeppenfeld, D. M., Simon, M., Haswell, J. D., D’Abreo, D., Murchison, C., Quinn, J. F., Grafe, M. R., Woltjer, R. L., Kaye, J., & Iliff, J. J. (2017) · JAMA Neurology · doi:10.1001/jamaneurol.2016.4370 · Cited by 651 · see citing works
“Since2013,wehavedefinedabrainwideperivascularpathway, termed the glymphatic system, that facilitates the recirculation of cerebrospinal fluid (CSF) through the brain parenchyma and supports the clearance of interstitial solutes including Aβ and tau.(3-7) Perivascular exchange of CSF and interstitial fluid is dependent…”
BackgroundSelf-citationImpaired glymphatic function and clearance of tau in an Alzheimer’s disease model
Harrison, I. F., Ismail, O., Machhada, A., Colgan, N. C., Ohene, Y., Nahavandi, P., Ahmed, Z., Fisher, A., Meftah, S., Murray, T. K., et al. (2020) · Brain · doi:10.1093/brain/awaa179 · Cited by 663 · see citing works
“Reactive astrogliosis, though common place in degenerative Alzheimer’s disease phenotypes, is associated with increased AQP4 expression, and reduced AQP4 polarization (Iliff et al., 2014; Kress et al., 2014).”
BackgroundMethodInfluentialUnderstanding the functions and relationships of the glymphatic system and meningeal lymphatics
Louveau, A., Plog, B. A., Antila, S., Alitalo, K., Nedergaard, M., & Kipnis, J. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90603 · Cited by 640 · see citing works
“Endothelial LRP1 transports amyloid-β(1-42) across the blood-brain barrier.”
BackgroundSelf-citationThe Brain’s Glymphatic System: Current Controversies
Mestre, H., Mori, Y., & Nedergaard, M. (2020) · Trends in Neurosciences · doi:10.1016/j.tins.2020.04.003 · Cited by 609 · see citing works
Self-citationRasmussen, M. K., Mestre, H., & Nedergaard, M. (2021) · Physiological Reviews · doi:10.1152/physrev.00031.2020 · Cited by 622 · see citing works
Self-citationSuppression of glymphatic fluid transport in a mouse model of Alzheimer's disease
Peng, W., Achariyar, T. M., Li, B., Liao, Y., Mestre, H., Hitomi, E., Regan, S., Kasper, T., Peng, S., Ding, F., et al. (2016) · Neurobiology of Disease · doi:10.1016/j.nbd.2016.05.015 · Cited by 580 · see citing works
“We also quantified Aβ clearance from the frontal cortex using the same radiolabeled approach (Deane et al., 2012; Iliff et al., 2012; Kress et al., 2014; Singh et al., 2013; Xie et al., 2013).”
InfluentialSelf-citationBrain-wide glymphatic enhancement and clearance in humans assessed with MRI.
Ringstad, G., Valnes, L. M., Dale, A. M., Pripp, A. H., Vatnehol, S.-A. S., Emblem, K. E., Mardal, K.-A., & Eide, P. K. (2018) · JCI Insight · doi:10.1172/jci.insight.121537 · Cited by 533 · see citing works
“Another important limitation of our comparison of iNPH patients with REF individuals is their different ages, and paravascular clearance has been shown to be impaired with ageing (22).”
The Glymphatic System and Waste Clearance with Brain Aging: A Review
Benveniste, H., Liu, X., Koundal, S., Sanggaard, S., Lee, H., & Wardlaw, J. (2019) · Gerontology · doi:10.1159/000490349 · Cited by 517 · see citing works
Toth, P., Tarantini, S., Csiszar, A., & Ungvari, Z. (2017) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00581.2016 · Cited by 522 · see citing works
Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits
Xu, Z., Xiao, N., Chen, Y., Huang, H., Marshall, C., Gao, J., Cai, Z., Wu, T., Hu, G., & Xiao, M. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0056-1 · Cited by 500 · see citing works
“Perivascular (or pia) AQP4 polarization was obtained by comparing expression ratios of AQP4 at perivascular (or pia surface) versus parenchymal domains [6, 41].”
Vasomotion as a Driving Force for Paravascular Clearance in the Awake Mouse Brain
van Veluw, S. J., Hou, S. S., Calvo-Rodríguez, M., Arbel‐Ornath, M., Snyder, A. C., Frosch, M. P., Greenberg, S. M., & Bacskai, B. J. (2019) · Neuron · doi:10.1016/j.neuron.2019.10.033 · Cited by 492 · see citing works
“Drainage of soluble waste products from the interstitial fluid (ISF) of the brain seems to be an important process to maintain brain health during aging (Xie et al., 2013; Kress et al., 2014; Benveniste et al., 2019).”
BackgroundInfluentialThe Meningeal Lymphatic System: A New Player in Neurophysiology
Da Mesquita, S., Fu, Z., & Kipnis, J. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.022 · Cited by 479 · see citing works
The Glymphatic System: A Novel Component of Fundamental Neurobiology
Hablitz, L. M., & Nedergaard, M. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0619-21.2021 · Cited by 480 · see citing works
“Upon feeding, the visceral branches of the vagus nerve are activated by a variety of neuroendocrine cues, including cholecystokinin (CCK) and glucagon-like peptide 1 (GLP-1), that are produced by enteroendocrine cells of the gut (Dockray, 2009; Krieger et al., 2015).”
BackgroundSelf-citationCD22 blockade restores homeostatic microglial phagocytosis in ageing brains
Pluvinage, J. V., Haney, M. S., Smith, B. A. H., Sun, J., Iram, T., Bonanno, L., Li, L., Lee, D. P., Morgens, D. W., Yang, A. C., et al. (2019) · Nature · doi:10.1038/s41586-019-1088-4 · Cited by 459 · see citing works
Kiviniemi, V. J., Wang, X., Korhonen, V. O., Keinänen, T., Tuovinen, T., Autio, J. A., LeVan, P., Keilholz, S. D., Zang, Y., Hennig, J., et al. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15622047 · Cited by 443 · see citing works
“A clinical platform capable of evaluating glymphatic pulsation mechanisms such as ultra-fast MREG in this study might open new possibilities in understanding the pathophysiological mechanisms behind glymphatic decline and protein accumulations in aging.(32)”
BackgroundSelf-citationAstrocytes in human central nervous system diseases: a frontier for new therapies
Verkhratsky, A., Butt, A., Li, B., Illes, P., Zorec, R., Semyanov, A., Tang, Y., & Sofroniew, M. V. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01628-9 · Cited by 428 · see citing works
“In the ageing brain, AQP4 migrates away from endfeet, which reduces operational capacity of the glymphatic system by ~40%.(546) Morphological atrophy of astrocytes also reduces their presence in the neuropil, which leads to an increase of extracellular diffusion channels and hence to an increase in mean diffusivity of…”
BackgroundThe Effect of Body Posture on Brain Glymphatic Transport
Lee, H. J., Xie, L., Yu, M., Kang, H., Feng, T., Deane, R., Logan, J., Nedergaard, M., & Benveniste, H. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.1625-15.2015 · Cited by 447 · see citing works
“The open end of the needle was inserted into a piece of polyethylene tubing, which was sealed by cauterization (Xie et al., 2013; Kress et al., 2014).”
MethodSelf-citationPerivascular spaces, glymphatic dysfunction, and small vessel disease
Mestre, H., Kostrikov, S., Mehta, R. I., & Nedergaard, M. (2017) · Clinical Science · doi:10.1042/cs20160381 · Cited by 403 · see citing works
“A loss in compliance would be expected to result in an increase in pulsatility, counter to the results seen in old mice(28).”
BackgroundMethodResultInfluentialSelf-citationGlymphatic System Impairment in Alzheimer’s Disease and Idiopathic Normal Pressure Hydrocephalus
Reeves, B. C., Karimy, J. K., Kundishora, A. J., Mestre, H., Cerci, H. M., Matouk, C., Alper, S. L., Lundgaard, I., Nedergaard, M., & Kahle, K. T. (2020) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2019.11.008 · Cited by 403 · see citing works
“Moreover, as progressive AQP4 depolarization occurs throughout physiological aging in mice [30], further age-matched studies of humans are needed to test the specificity of pathologic AQP4 depolarization specific for iNPH or other neurodegenerative disorders, as opposed to the normal aging process.”
BackgroundInfluentialSelf-citationAstrocytes in physiological aging and Alzheimer’s disease
Rodríguez-Arellano, J. J., Parpura, V., Zorec, R., & Verkhratsky, A. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.01.007 · Cited by 439 · see citing works
Zou, W., Pu, T., Feng, W., Lu, M., Zheng, Y., Du, R., Xiao, M., & Hu, G. (2019) · Translational Neurodegeneration · doi:10.1186/s40035-019-0147-y · Cited by 396 · see citing works
“was obtained by the ratio between the AQP4 fluorescence intensity of the perivascular domains and the adjacent neutrophil domains [27, 28].”
BackgroundKamagata, K., Andica, C., Takabayashi, K., Saito, Y., Taoka, T., Nozaki, H., Kikuta, J., Fujita, S., Hagiwara, A., Kamiya, K., et al. (2022) · Neurology · doi:10.1212/wnl.0000000000201300 · Cited by 393 · see citing works
“The glymphatic system has been suggested to be an essential component of Aβ clearance in the brain of rodents.(3,4) Glymphatic dysfunction has been found to be correlated with Aβ accumulation; however, its involvement in the pathogenesis of Alzheimer disease in humans is yet to be fully understood.”
BackgroundChanges in the composition of brain interstitial ions control the sleep-wake cycle
Ding, F., O’Donnell, J., Xu, Q., Kang, N., Goldman, N., & Nedergaard, M. (2016) · Science · doi:10.1126/science.aad4821 · Cited by 383 · see citing works
“Iontophoretic tetramethylammonium (TMA) quantification of the extracellular space volume All experimental procedures were adapted from previous studies (10, 11, 28, 34-37).”
MethodSelf-citationHe, X.-F., Liu, D.-X., Zhang, Q., Liang, F.-Y., Dai, G.-Y., Zeng, J.-S., Pei, Z., Xu, G.-Q., & Lan, Y. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00144 · Cited by 371 · see citing works
“The paravascular bulk flow of the CSF and ISF is supported by the astroglial water channel AQP4 (Kress et al., 2014), which localizes to the perivascular astrocytic Frontiers in Molecular Neuroscience | www.frontiersin.org 11 May 2017 | Volume 10 | Article 144 end feet ensheathing the cerebral…”
BackgroundMethodThe glymphatic system: Current understanding and modeling
Bohr, T., Hjorth, P. G., Holst, S. C., Hrabětová, S., Kiviniemi, V. J., Lilius, T. O., Lundgaard, I., Mardal, K., Martens, E. A., Mori, Y., et al. (2022) · iScience · doi:10.1016/j.isci.2022.104987 · Cited by 381 · see citing works
Self-citationImpaired meningeal lymphatic drainage in patients with idiopathic Parkinson’s disease
Ding, X., Wang, X., Xia, D., Liu, H., Tian, H., Fu, Y., Chen, Y., Qin, C., Wang, J.-Q., Zhang, Z., et al. (2021) · Nature Medicine · doi:10.1038/s41591-020-01198-1 · Cited by 359 · see citing works
Bakker, E. N. T. P., Bacskai, B. J., Arbel-Ornath, M., Aldea, R., Bedussi, B., Morris, A. W. J., Weller, R. O., & Carare, R. O. (2016) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-015-0273-8 · Cited by 353 · see citing works
“These values remain unaffected by increasing age, despite that fact that ageing results in profound morphological changes of the cells of the grey matter (Kress et al. 2014).”
BackgroundInfluentialMultisensory gamma stimulation promotes glymphatic clearance of amyloid
Murdock, M. H., Yang, C.-Y., Sun, N., Pao, P., Blanco‐Duque, C., Kahn, M. C., Kim, T., Lavoie, N., Victor, M. B., Islam, R., et al. (2024) · Nature · doi:10.1038/s41586-024-07132-6 · Cited by 370 · see citing works
“We used established methods to quantify AQP4 polarization 12,21 .”
BackgroundMethodLymphatic Vessel Network Structure and Physiology
Breslin, J. W., Yang, Y., Scallan, J. P., Sweat, R. S., Adderley, S., & Murfee, W. L. (2018) · Comprehensive physiology · doi:10.1002/cphy.c180015 · Cited by 402 · see citing works
Alves de Lima, K., Rustenhoven, J., & Kipnis, J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-102319-103410 · Cited by 348 · see citing works
Simon, M. J., & Iliff, J. J. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2015.10.014 · Cited by 339 · see citing works
“However, perivascular AQP4 localization was also markedly reduced in the aging brain and was significantly associated with slowing of perivascular CSF influx into and through the brain parenchyma [6].”
BackgroundSelf-citationUnderstanding the role of the perivascular space in cerebral small vessel disease
Brown, R., Benveniste, H., Black, S. E., Charpak, S., Dichgans, M., Joutel, A., Nedergaard, M., Smith, K. J., Zloković, B. V., & Wardlaw, J. M. (2018) · Cardiovascular Research · doi:10.1093/cvr/cvy113 · Cited by 342 · see citing works
Self-citationSmith, A. J., Yao, X., Dix, J. A., Jin, B.-J., & Verkman, A. S. (2017) · eLife · doi:10.7554/elife.27679 · Cited by 362 · see citing works
“As there may be regional differences in tracer penetration throughout the brain (Kress et al., 2014), we measured fractional tracer penetration in serial coronal sections made at 100 mm intervals through the brain.”
MethodCerebrospinal fluid dynamics and intracranial pressure elevation in neurological diseases
Bothwell, S. W., Janigro, D., & Patabendige, A. (2019) · Fluids and Barriers of the CNS · doi:10.1186/s12987-019-0129-6 · Cited by 331 · see citing works
Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
Hauglund, N. L., Andersen, M., Tokarska, K., Radovanovic, T., Kjærby, C., Sørensen, F., Bojarowska, Z., Untiet, V., Ballestero, S. B., Kolmos, M. G., et al. (2025) · Cell · doi:10.1016/j.cell.2024.11.027 · Cited by 341 · see citing works
Self-citationTissue mechanics regulate brain development, homeostasis and disease
Barnes, J. M., Przybyla, L., & Weaver, V. M. (2017) · Journal of Cell Science · doi:10.1242/jcs.191742 · Cited by 313 · see citing works
“Slowing of CSF flux through the brain is also associated with increasing age (Kress et al., 2014), which might affect cell functions that are dependent on sensing shear flow.”
BackgroundImpairment of the Glymphatic Pathway and Putative Meningeal Lymphatic Vessels in the Aging Human
Zhou, Y., Cai, J., Zhang, W., Gong, X., Yan, S., Zhang, K., Luo, Z., Sun, J., Jiang, Q., & Lou, M. (2020) · Annals of Neurology · doi:10.1002/ana.25670 · Cited by 305 · see citing works
“Our finding that the glymphatic pathway was impaired in the aging human brain is in agreement with multiple previous studies.(8,9) Aging has been considered as an essential factor in the regulation of the brain”
ResultSleep Disturbance, Cognitive Decline, and Dementia: A Review
Wu, M. N., Rosenberg, P. B., Spira, A. P., & Wennberg, A. M. V. (2017) · Seminars in Neurology · doi:10.1055/s-0037-1604351 · Cited by 310 · see citing works
Sun, Y., Koyama, Y., & Shimada, S. (2022) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2022.903455 · Cited by 304 · see citing works
Emerging roles for dynamic aquaporin-4 subcellular relocalization in CNS water homeostasis
Salman, M. M., Kitchen, P., Halsey, A., Wang, M. X., Törnroth-Horsefield, S., Conner, A. C., Badaut, J., Iliff, J. J., & Bill, R. M. (2022) · Brain · doi:10.1093/brain/awab311 · Cited by 303 · see citing works
“In each case, impairment of perivascular exchange was associated with a reduction in the cell-level localization of AQP4 to perivascular processes.(57,61,62) When this perivascular localization of AQP4 is disrupted by deletion of the Snta1 gene, glymphatic function is similarly impaired.”
BackgroundSelf-citationHealthy aging and the blood–brain barrier
Banks, W. A., Reed, M. J., Logsdon, A. F., Rhea, E. M., & Erickson, M. A. (2021) · Nature Aging · doi:10.1038/s43587-021-00043-5 · Cited by 293 · see citing works
Impaired Glymphatic Transport in Spontaneously Hypertensive Rats
Mortensen, K. N., Sanggaard, S., Mestre, H., Lee, H., Kostrikov, S., Xavier, A. L. R., Gjedde, A., Benveniste, H., & Nedergaard, M. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1974-18.2019 · Cited by 266 · see citing works
“Whereas previous studies have used amount of brain tracer uptake and area coverage as markers of glymphatic influx (Iliff et al., 2012, 2013a; Kress et al., 2014; Plog et al., 2015; Peng et al., 2016), the present study shows that brain tracer concentrations after CM tracer infusion depend on the efficacy of the glymp…”
BackgroundMethodResultInfluentialSelf-citationGlymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration
Ishida, K., Yamada, K., Nishiyama, R., Hashimoto, T., Nishida, I., Abe, Y., Yasui, M., & Iwatsubo, T. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20211275 · Cited by 291 · see citing works
“impaired in aged brain (Kress et al., 2014) and also associated with”
Cerebral small vessel disease: Capillary pathways to stroke and cognitive decline
Østergaard, L., Engedal, T. S., Moreton, F. C., Hansen, M. B., Wardlaw, J. M., Dalkara, T., Markus, H. S., & Muir, K. W. (2015) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1177/0271678x15606723 · Cited by 283 · see citing works
“Indeed, impaired glymphatic clearance has recently emerged as a potential therapeutic target.(58) Located in the layers of capillary basement membrane, pericytes are therefore exposed to amyloid during its perivascular removal and clearance across the BBB.”
BackgroundDeciphering the astrocyte reaction in Alzheimer's disease
Perez-Nievas, B. G., & Serrano-Pozo, A. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00114 · Cited by 282 · see citing works
“This common mechanism could explain the finding of calcium overload (Kuchibhotla et al., 2008) and hyperactive neurons (Busche et al., 2008, 2012) found in the proximity of plaques using multiphoton calcium imaging in live APP/PS1 mice, although the latter finding was attributed to a decreased…”
BackgroundGlymphatic system impairment in multiple sclerosis: relation with brain damage and disability
Carotenuto, A., Cacciaguerra, L., Pagani, E., Preziosa, P., Filippi, M., & Rocca, M. A. (2021) · Brain · doi:10.1093/brain/awab454 · Cited by 280 · see citing works
Clearance of cerebral Aβ in Alzheimer’s disease: reassessing the role of microglia and monocytes
Zuroff, L. R., Daley, D. A., Black, K. L., & Koronyo‐Hamaoui, M. (2017) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-017-2463-7 · Cited by 275 · see citing works
“Advanced age also reduced glymphatic clearance rates in murine models, perhaps due to an age-dependent loss of AQP4 polarization [294].”
BackgroundSimon, M. J., Wang, M. X., Ismail, O., Braun, M., Schindler, A. G., Reemmer, J., Wang, Z., Haveliwala, M. A., O’Boyle, R. P., Han, W., et al. (2022) · Alzheimer s Research & Therapy · doi:10.1186/s13195-022-00999-5 · Cited by 287 · see citing works
“We next sought to replicate and extend findings from our prior study [13] to define whether similar changes in AQP4 localization are observed in the aging rodent brain as are observed in aging and AD human subjects ([20], Fig.”
BackgroundMethodResultInfluentialSelf-citationPhysical Exercise Inhibits Inflammation and Microglial Activation
Mee-inta, O., Zhao, Z., & Kuo, Y. (2019) · Cells · doi:10.3390/cells8070691 · Cited by 270 · see citing works
“Impaired glymphatic function is evident in aging and neurodegenerative diseases [118,119].”
BackgroundBanerjee, G., Kim, H. J., Fox, Z. V., Jäger, H. R., Wilson, D., Charidimou, A., Na, H. K., Na, D. L., Seo, S. W., & Werring, D. J. (2017) · Brain · doi:10.1093/brain/awx003 · Cited by 255 · see citing works
“Alternatively CAA may disrupt perivascular drainage via perturbations in normal arteriolar pulsation (Hawkes et al., 2014; Kress et al., 2014).”
BackgroundLymphatic drainage system of the brain: A novel target for intervention of neurological diseases
Sun, B., Wang, L.-H., Yang, T., Sun, J., Mao, L., Yang, M., Yuan, H., Colvin, R. A., & Yang, X. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2017.08.007 · Cited by 255 · see citing works
Achariyar, T. M., Li, B., Peng, W., Verghese, P. B., Shi, Y., McConnell, E., Benraiss, A., Kasper, T., Song, W., Takano, T., et al. (2016) · Molecular Neurodegeneration · doi:10.1186/s13024-016-0138-8 · Cited by 250 · see citing works
“the wake state [27], aging [42] and in brain injury and trauma [46, 73], could reduce the delivery and distribution of apoE to brain, which may lead to apoE related disorder in the long-term.”
BackgroundMethodSelf-citationCerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET
de Leon, M. J., Li, Y., Okamura, N., Tsui, W. H., Saint-Louis, L. A., Glodzik, L., Osorio, R. S., Fortea, J., Butler, T., Pirraglia, E., et al. (2017) · Journal of Nuclear Medicine · doi:10.2967/jnumed.116.187211 · Cited by 246 · see citing works
“Suggesting CSF clearance abnormalities in AD, impaired glymphatic CSF clearance was recently observed in aged wild-type mice (5) and in an AD mouse model (6).”
BackgroundSelf-citationCerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels
Mazzitelli, J. A., Smyth, L. C. D., Cross, K. A., Dykstra, T., Sun, J., Du, S., Mamuladze, T., Smirnov, I., Rustenhoven, J., & Kipnis, J. (2022) · Nature Neuroscience · doi:10.1038/s41593-022-01029-1 · Cited by 253 · see citing works
Schain, A. J., Melo‐Carrillo, A., Strassman, A. M., & Burstein, R. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.3390-16.2017 · Cited by 254 · see citing works
The glymphatic hypothesis: the theory and the evidence
Hladky, S. B., & Barrand, M. A. (2022) · Fluids and Barriers of the CNS · doi:10.1186/s12987-021-00282-z · Cited by 271 · see citing works
“These factors include: knockout of AQP4 [11]; sleep [37]; anaesthesia (especially that incorporating the α2 adrenoceptor agonists xylazine or medetomidine) [37, 201]; traumatic brain injury [15]; age [177]; posture [202]; ablation of meningeal lymphatics [203]; small vessel disease [19]; idi‐ opathic normal pressure h…”
BackgroundThe glymphatic system: implications for drugs for central nervous system diseases
Lohela, T. J., Lilius, T. O., & Nedergaard, M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00500-9 · Cited by 246 · see citing works
Self-citationAstrocyte Endfeet in Brain Function and Pathology: Open Questions
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BackgroundNeurodegenerative Diseases: Regenerative Mechanisms and Novel Therapeutic Approaches
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Background
- Authors
- Kress, B. T., Iliff, J. J., Xia, M., Wang, M., Wei, H. S., Zeppenfeld, D., Xie, L., Kang, H., Xu, Q., Liew, J. A., Plog, B. A., Ding, F., Deane, R., & Nedergaard, M.
- Affiliations
- University of Rochester Medicine (US)
- Oregon Health & Science University (US)
- Corresponding author
- Iliff, Jeffrey J.
- ORCID
- Venue
- Annals of Neurology
- Publisher
- Wiley
- Published
- 2014-09-26
- Volume
- 76
- Issue
- 6
- Pages
- 845-861
- ISSN
- 0364-5134 (ISSN-L)
- 1531-8249
- PMC
- PMC4245362
- OpenAlex
- W2100314515
- Cited by
- 1,521
- References
- 42
- Citations by year
- 2026: 182 · 2025: 186 · 2024: 202 · 2023: 167 · 2022: 172 · 2021: 126 · 2020: 126 · 2019: 98 · 2018: 89 · 2017: 70 · 2016: 54 · 2015: 47 · 2014: 1
- FWCI
- 26.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Annals of Neurology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association (12SDG11820014)
- National Institutes of Health (F32 NS073373)
- Oregon Partnership for Alzheimer's Research
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- glymphatic system, brain aging, aquaporin-4, astrocytes, amyloid-beta clearance, cognitive decline, neurodegenerative diseases
- MeSH terms
- Aging, Animals, Brain, Cerebrovascular Circulation, Female, Male, Metabolic Clearance Rate, Mice, Inbred C57BL, Neuroglia, Microscopy, Fluorescence, Multiphoton, Mice, Aquaporin 4
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