Nörolojik Hastalıklarda Gilenfatik Sistemin Rolü: Güncel Bulgular ve Geleceğe Yönelik Araştırmalar

Özlem Totuk; Güldeniz Çetin; Şevki Sahin

doi:10.17827/aktd.1533741

EN TR

The Role of the Glymphatic System in Neurological Diseases: Current Findings and Future Research

Abstract

Glymphatic system (GS) is a drainage system formed by glial cells that removes waste and soluble molecules from the brain interstitial space through the cerebrospinal fluid. Just as it plays an important role in the pathology of neurodegenerative diseases, it also has a function in all neurological diseases. Failure to remove waste materials is one of the most important causes of chronic neuroinflammation in neurodegenerative diseases. Aging, sleep, inflammation and various diseases negatively affect the function of the glymphatic system. Studies on the modulation of Aquaporin 4 channels in neurodegenerative diseases have shown promising results regarding the dysfunctions of this system. This review aims to present the current information on the functioning of GS, the factors that cause its deterioration and its relationship with neurological diseases such as Alzheimer's disease (AD), Parkinson's Disease (PD), Huntington's disease (HD), normal pressure hydrocephalus (NBH), stroke, epilepsy, amyotrophic diseases, etc. It summarizes the focus on disease groups such as lateral sclerosis (ALS), multiple sclerosis (MS), neuromyelitis optica spectrum diseases (NMOSD), migraine, idiopathic intracranial hypertension (IIH), and traumatic brain injury (TBI).

Keywords

Glymphatic system , neurodegenerative disease , headache , demyelinating disease , epilepsy , stroke.

Nörolojik Hastalıklarda Gilenfatik Sistemin Rolü: Güncel Bulgular ve Geleceğe Yönelik Araştırmalar

Öz

Gilenfatik sistem (GS), glial hücreler tarafından oluşturulan, beyin omurilik sıvısı aracılığı ile beyin interstisyel alandan atık ve çözünebilir moleküllerin uzaklaştırılmasını sağlayan bir drenaj sistemidir. Nörodejeneratif hastalıkların patolojisinde önemli bir rol oynadığı gibi tüm nörolojik hastalıklarda da fonksiyonu mevcuttur. Atık maddelerin uzaklaştırılamaması nörodejeneratif hastalıklarda kronik nöroinflamasyonun en önemli sebeplerinden birisidir. Yaşlanma, uyku, inflamasyon ve çeşitli hastalıklar gilenfatik sistemin fonksiyonunu olumsuz etkiler. Nörodejeneratif hastalıklarda Aquaporin 4 kanallarının modülasyonu üzerine yapılan çalışmalar bu sistemin işlev bozukluklarına dair umut vadeden sonuçlar göstermiştir. Bu derleme, GS’in işleyişi, bozulmasına neden olan faktörler ve nörolojik hastalıklar ile ilişkisi üzerine mevcut bilgileri Alzheimer hastalığı (AH), Parkinson Hastalığı (PH), Huntington hastalığı (HH), normal basınçlı hidrosefali (NBH), inme, epilepsi, amiyotrofik lateral skleroz (ALS), multipl skleroz (MS), nöromiyelitis optika spektrum hastalıkları (NMOSH), migren, idiyopatik intrakraniyal hipertansiyon (İİH), travmatik beyin hasarı (TBH) odak hastalık grupları üzerinden özetlemektedir.

Anahtar Kelimeler

Gilenfatik sistem , nörodejeneratif hastalık , başağrısı , demiyelinizan hastalık , epilepsi , inme

Kaynakça

1. Nedergaard M. Neuroscience. Garbage truck of the brain. Science (New York, N.Y.). 2013;340(6140):1529–1530.
2. Lecco, V. Probable modification of the lymphatic fissures of the walls of the venous sinuses of the dura mater. Archivio Italiano di Otologia, Rinologia e Laringologia. 1953;64(3), 287-296.
3. Hablitz LM, Nedergaard M. (2021). The Glymphatic System: A Novel Component of Fundamental Neurobiology. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2021;41(37), 7698–7711.
4. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Science translational medicine. 2012;4(147), 147ra111.
5. Hladky SB, Barrand MA. The glymphatic hypothesis: the theory and the evidence. Fluids and barriers of the CNS. 2022;19(1), 9.
6. Cooper JM, Lathuiliere A, Migliorini M, Arai AL, Wani MM, Dujardin S et al. Regulation of tau internalization, degradation, and seeding by LRP1 reveals multiple pathways for tau catabolism. The Journal of biological chemistry. 2021;296, 100715.
7. Kylkilahti TM, Berends E, Ramos M, Shanbhag NC, Töger J, Markenroth Bloch K et al. Achieving brain clearance and preventing neurodegenerative diseases-A glymphatic perspective. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2021;41(9), 2137–2149.
8. Pascoal TA, Benedet AL, Ashton NJ, Kang MS, Therriault J, Chamoun M et al. Microglial activation and tau propagate jointly across Braak stages. Nature medicine. 2021;27(9), 1592–1599. 9. Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y et al. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. The Journal of experimental medicine. 2022;219(3), e20211275.
10. Suresh S, Larson J, Jenrow KA. Chronic neuroinflammation impairs waste clearance in the rat brain. Frontiers in neuroanatomy. 2022;16, 1013808.
11. Liu H, Luo Y, Zhao S, Tan J, Chen M, Liu X et al. A reactive oxygen species-related signature to predict prognosis and aid immunotherapy in clear cell renal cell carcinoma. Frontiers in oncology. 2023;13, 1202151.

12. Kepp O, Galluzzi L, Zitvogel L, Kroemer G. Pyroptosis - a cell death modality of its kind?. European journal of immunology. 2010;40(3), 627–630.
13. Thomsen MS, Routhe LJ, Moos T. The vascular basement membrane in the healthy and pathological brain. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2017;37(10), 3300–3317.
14. de Leon MJ, Li Y, Okamura N, Tsui WH, Saint-Louis LA, Glodzik L et al. Cerebrospinal Fluid Clearance in Alzheimer Disease Measured with Dynamic PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2017;58(9), 1471–1476.
15. Reeves BC, Karimy JK, Kundishora AJ, Mestre H, Cerci HM, Matouk C et al. Glymphatic System Impairment in Alzheimer's Disease and Idiopathic Normal Pressure Hydrocephalus. Trends in molecular medicine. 2020;26(3), 285–295.
16. Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science (New York, N.Y.). 2009;326(5955), 1005–1007.
17. Da Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FG, Wall M et al. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature. 2021;593(7858), 255–260.
18. Pappolla M, Sambamurti K, Vidal R, Pacheco-Quinto J, Poeggeler B, Matsubara E. Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice. Neurobiology of disease. 2014;71, 215–219.
19. Cui H, Wang W, Zheng X, Xia D, Liu H, Qin C et al. Decreased AQP4 Expression Aggravates ɑ-Synuclein Pathology in Parkinson's Disease Mice, Possibly via Impaired Glymphatic Clearance. Journal of molecular neuroscience : MN. 2021;71(12), 2500–2513.
20. Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y et al. Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013;33(46), 18190–18199.
21. Eide PK, Sorteberg W. Diagnostic intracranial pressure monitoring and surgical management in idiopathic normal pressure hydrocephalus: a 6-year review of 214 patients. Neurosurgery. 2010;66(1), 80–91.
22. Greitz D. Radiological assessment of hydrocephalus: new theories and implications for therapy. Neurosurgical review. 2004;27(3), 145–167.
23. Eide PK, Ringstad G. Delayed clearance of cerebrospinal fluid tracer from entorhinal cortex in idiopathic normal pressure hydrocephalus: A glymphatic magnetic resonance imaging study. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2019;39(7), 1355–1368.
24. Rosell A, Cuadrado E, Ortega-Aznar A, Hernández-Guillamon M, Lo EH, Montaner J. MMP-9-positive neutrophil infiltration is associated to blood-brain barrier breakdown and basal lamina type IV collagen degradation during hemorrhagic transformation after human ischemic stroke. Stroke. 2008;39(4), 1121–1126.
25. Kim ST, Kim SE, Lee DA, Lee HJ, Park KM. Anti-seizure medication response and the glymphatic system in patients with focal epilepsy. European journal of neurology. 2024;31(1), e16097.
26. Liu H, Chen L, Zhang C, Liu C, Li Y, Cheng L et al. Interrogation of dynamic glucose-enhanced MRI and fluorescence-based imaging reveals a perturbed glymphatic network in Huntington’s disease. bioRxiv, 2023-04.
27. Zamani A, Walker AK, Rollo B, Ayers KL, Farah R, O'Brien TJ et al. Impaired glymphatic function in the early stages of disease in a TDP-43 mouse model of amyotrophic lateral sclerosis. Translational neurodegeneration. 2022;11(1), 17.
28. Zou S, Lan YL, Wang H, Zhang B, Sun YG. The potential roles of aquaporin 4 in amyotrophic lateral sclerosis. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2019;40(8), 1541–1549.
29. Mestre H, Hablitz LM, Xavier AL, Feng W, Zou W, Pu T et al. Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife. 2018;7, e40070.
30. Fournier AP, Gauberti M, Quenault A, Vivien D, Macrez R, Docagne F. Reduced spinal cord parenchymal cerebrospinal fluid circulation in experimental autoimmune encephalomyelitis. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism. 2019;39(7), 1258–1265.
31. Schubert JJ, Veronese M, Marchitelli L, Bodini B, Tonietto M, Stankoff B et al. Dynamic 11C-PiB PET Shows Cerebrospinal Fluid Flow Alterations in Alzheimer Disease and Multiple Sclerosis. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2019;60(10), 1452–1460.
32. Rohr SO, Greiner T, Joost S, Amor S, Valk PV, Schmitz C et al. Aquaporin-4 Expression during Toxic and Autoimmune Demyelination. Cells. 2020;9(10), 2187.
33. Aharoni R, Eilam R, Arnon R. Astrocytes in Multiple Sclerosis-Essential Constituents with Diverse Multifaceted Functions. International journal of molecular sciences. 2021;22(11), 5904.
34. Alghanimy A, Work LM, Holmes WM. The glymphatic system and multiple sclerosis: An evolving connection. Multiple sclerosis and related disorders. 2024;83, 105456.
35. Vittorini MG, Sahin A, Trojan A, Yusifli S, Alashvili T, Bonifácio GV et al. The glymphatic system in migraine and other headaches. The journal of headache and pain. 2024;25(1), 34.
36. Gu S, Li Y, Jiang Y, Huang JH, Wang F. Glymphatic Dysfunction Induced Oxidative Stress and Neuro-Inflammation in Major Depression Disorders. Antioxidants (Basel, Switzerland). 2022;11(11), 2296.
37. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Annals of neurology. 1990;28(2), 183–187.
38. Nicholson P, Kedra A, Shotar E, Bonnin S, Boch AL, Shor N et al. Idiopathic Intracranial Hypertension: Glymphedema of the Brain. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2021;41(1), 93–97.
39. Lenck S, Vallée F, Labeyrie MA, Touitou V, Saint-Maurice JP, Guillonnet A et al. Stenting of the Lateral Sinus in Idiopathic Intracranial Hypertension According to the Type of Stenosis. Neurosurgery. 2017;80(3), 393–400.
40. Christensen J, Yamakawa GR, Shultz SR, Mychasiuk R. Is the glymphatic system the missing link between sleep impairments and neurological disorders? Examining the implications and uncertainties. Progress in neurobiology. 2021;198, 101917.
41. Vandebroek A, Yasui M. Regulation of AQP4 in the Central Nervous System. International journal of molecular sciences. 2020;21(5), 1603.
42. Kitchen P, Salman MM, Halsey AM, Clarke-Bland C, MacDonald JA, Ishida H et al. Targeting Aquaporin-4 Subcellular Localization to Treat Central Nervous System Edema. Cell. 2020;181(4), 784–799.e19.
43. Silva I, Silva J, Ferreira R, Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer's disease. Neurological research and practice. 2021;3(1), 5.
44. He XF, Liu DX, Zhang Q, Liang FY, Dai GY, Zeng JS et al. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice. Frontiers in molecular neuroscience. 2017;10, 144.
45. Ren H, Luo C, Feng Y, Yao X, Shi Z, Liang F et al. Omega-3 polyunsaturated fatty acids promote amyloid-β clearance from the brain through mediating the function of the glymphatic system. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2017;31(1), 282–293.
46. Nedergaard M, Goldman SA. Glymphatic failure as a final common pathway to dementia. Science (New York, N.Y.). 2020;370(6512), 50–56.
47. Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D et al. Impairment of paravascular clearance pathways in the aging brain. Annals of neurology. 2014;76(6), 845–861.
48. Ju YS, Ooms SJ, Sutphen C, Macauley SL, Zangrilli MA, Jerome G et al. Slow wave sleep disruption increases cerebrospinal fluid amyloid-β levels. Brain : a journal of neurology. 2017;140(8), 2104–2111.
49. Zuzuárregui JRP, During EH. Sleep Issues in Parkinson's Disease and Their Management. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2020;17(4), 1480–1494.
50. Ju YE, McLeland JS, Toedebusch CD, Xiong C, Fagan AM, Duntley SP et al. Sleep quality and preclinical Alzheimer disease. JAMA neurology. 2013;70(5), 587–593.
51. Xu W, Wang H, Wan Y, Tan C, Li J, Tan L et al. Alcohol consumption and dementia risk: a dose-response meta-analysis of prospective studies. European journal of epidemiology. 2017;32(1), 31–42.
52. Mortensen KN, Sanggaard S, Mestre H, Lee H, Kostrikov S, Xavier ALR et al. Impaired Glymphatic Transport in Spontaneously Hypertensive Rats. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2019;39(32), 6365–6377.
53. Si X, Guo T, Wang Z, Fang Y, Gu L, Cao L et al. Neuroimaging evidence of glymphatic system dysfunction in possible REM sleep behavior disorder and Parkinson's disease. NPJ Parkinson's disease. 2022;8(1), 54.
54. Li Y, Rusinek H, Butler T, Glodzik L, Pirraglia E, Babich J et al. Decreased CSF clearance and increased brain amyloid in Alzheimer's disease. Fluids and barriers of the CNS. 2022;19(1), 21.
55. Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. The Lancet. Neurology. 2013;12(8), 822–838.
56. Aribisala BS, Wiseman S, Morris Z, Valdés-Hernández MC, Royle NA, Maniega, SM et al. Circulating inflammatory markers are associated with magnetic resonance imaging-visible perivascular spaces but not directly with white matter hyperintensities. Stroke. 2014;45(2), 605–607.
57. Huber VJ, Igarashi H, Ueki S, Kwee IL, Nakada T. Aquaporin-4 facilitator TGN-073 promotes interstitial fluid circulation within the blood–brain barrier:[: 17: O] H: 2: O JJVCPE MRI study. Neuroreport. 2018;29(9), 697-703.
58. Sun C, Lin L, Yin L, Hao X, Tian J, Zhang X et al. Acutely Inhibiting AQP4 With TGN-020 Improves Functional Outcome by Attenuating Edema and Peri-Infarct Astrogliosis After Cerebral Ischemia. Frontiers in immunology. 2022;13, 870029.
59. Jha RM, Raikwar SP, Mihaljevic S, Casabella AM, Catapano JS, Rani A et al. Emerging therapeutic targets for cerebral edema. Expert opinion on therapeutic targets. 2021;25(11), 917–938.
60. Sadana P, Coughlin L, Burke J, Woods R, Mdzinarishvili A. Anti-edema action of thyroid hormone in MCAO model of ischemic brain stroke: Possible association with AQP4 modulation. Journal of the neurological sciences. 2015;354(1-2), 37–45.
61. Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N et al. Melatonin: Pharmacology, Functions and Therapeutic Benefits. Current neuropharmacology. 2017;15(3), 434–443.
62. Pappolla MA, Matsubara E, Vidal R, Pacheco-Quinto J, Poeggeler B, Zagorski M et al. Melatonin Treatment Enhances Aβ Lymphatic Clearance in a Transgenic Mouse Model of Amyloidosis. Current Alzheimer research, 15(7). 2018;637–642.
63. Zhao G, Han H, Yang J, Sun M, Cui D, Li Y et al. Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium. Science China. Life sciences. 2020;63(9), 1363–1379.
64. Semyachkina-Glushkovskaya O, Postnov D, Penzel T, Kurths J. Sleep as a Novel Biomarker and a Promising Therapeutic Target for Cerebral Small Vessel Disease: A Review Focusing on Alzheimer's Disease and the Blood-Brain Barrier. International journal of molecular sciences. 2020;21(17), 6293.
65. Lazarus M, Oishi Y, Bjorness TE, Greene RW. Gating and the Need for Sleep: Dissociable Effects of Adenosine A1 and A2A Receptors. Frontiers in neuroscience. 2019;13, 740.
66. Zhao ZA, Li P, Ye SY, Ning YL, Wang H, Peng Y et al. Perivascular AQP4 dysregulation in the hippocampal CA1 area after traumatic brain injury is alleviated by adenosine A2A receptor inactivation. Scientific reports. 2017;7(1), 2254.
67. Semyachkina-Glushkovskaya O, Abdurashitov A, Dubrovsky A, Klimova M, Agranovich I, Terskov A et al. Photobiomodulation of lymphatic drainage and clearance: perspective strategy for augmentation of meningeal lymphatic functions. Biomedical optics express. 2020;11(2), 725–734.
68. Lin Y, Jin J, Lv R, Luo Y, Dai W, Li W et al. Repetitive transcranial magnetic stimulation increases the brain's drainage efficiency in a mouse model of Alzheimer's disease. Acta neuropathologica communications. 2021;9(1), 102.

Ayrıntılar

Birincil Dil

Türkçe

Konular

Nöroloji ve Nöromüsküler Hastalıklar

Bölüm

Derleme

Yazarlar

Özlem Totuk ^*
0000-0001-7274-025X
Türkiye

Güldeniz Çetin
0000-0001-9042-7697
Türkiye

Şevki Sahin
0000-0003-2016-9965
Türkiye

Yayımlanma Tarihi

24 Aralık 2025

Gönderilme Tarihi

16 Ağustos 2024

Kabul Tarihi

3 Aralık 2025

Yayımlandığı Sayı

Yıl 2025 Cilt: 34 Sayı: 4

DOI

https://doi.org/10.17827/aktd.1533741

IZ

https://izlik.org/JA28DA36ET

AMA

1.Totuk Ö, Çetin G, Sahin Ş. Nörolojik Hastalıklarda Gilenfatik Sistemin Rolü: Güncel Bulgular ve Geleceğe Yönelik Araştırmalar. aktd. 2025;34(4):253-261. doi:10.17827/aktd.1533741

The Role of the Glymphatic System in Neurological Diseases: Current Findings and Future Research

Abstract

Keywords

Nörolojik Hastalıklarda Gilenfatik Sistemin Rolü: Güncel Bulgular ve Geleceğe Yönelik Araştırmalar

Öz

Anahtar Kelimeler

Kaynakça

Ayrıntılar

Birincil Dil

Konular

Bölüm

Yazarlar

Yayımlanma Tarihi

Gönderilme Tarihi

Kabul Tarihi

Yayımlandığı Sayı

DOI

IZ

Kaynak Göster