Abstract
Glymphatic system denotes a brain-wide pathway that eliminates extracellular solutes from brain. It is driven by the flow of brain interstitial fluid (ISF) and cerebrospinal fluid (CSF) via perivascular spaces. Glymphatic convective flow is driven by cerebral arterial pulsation, which is facilitated by a water channel, aquaporin-4 (AQP4) expressed in astrocytic end-foot processes. Since its discovery, the glymphatic system receives a considerable scientific attention due to its pivotal role in clearing metabolic waste as well as neurotoxic substances such as amyloid b peptide. Tau is a microtubule binding protein, however it is also physiologically released into extracellular fluids. The presence of tau in the blood stream indicates that it is eventually cleared from the brain to the periphery, however, the detailed mechanisms that eliminate extracellular tau from the central nervous system remained to be elucidated. Recently, we and others have reported that extracellular tau is eliminated from the brain to CSF by an AQP4 dependent mechanism, suggesting the involvement of the glymphatic system. In this chapter, we describe the detailed protocol of how we can assess glymphatic outflow of tau protein from brain to CSF in mice.
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References
Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A Paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 4:147ra111. https://doi.org/10.1126/scitranslmed.3003748
Iliff JJ, Wang M, Zeppenfeld DM, Venkataraman A, Plog BA, Liao Y, Deane R, Nedergaard M (2013) Cerebral arterial pulsation drives paravascular CSF-interstitial fluid exchange in the murine brain. J Neurosci 33:18190–18199. https://doi.org/10.1523/JNEUROSCI.1592-13.2013
Mestre H, Hablitz LM, Xavier ALR, Feng W, Zou W, Pu T, Monai H, Murlidharan G, Rivera RMC, Simon MJ, Pike MM, Plá V, Du T, Kress BT, Wang X, Plog BA, Thrane AS, Lundgaard I, Abe Y, Yasui M, Thomas JH, **ao M, Hirase H, Asokan A, Iliff JJ, Nedergaard M (2018) Aquaporin-4-dependent glymphatic solute transport in the rodent brain. eLife 7:1–31. https://doi.org/10.7554/eLife.40070
Ringstad G, Valnes LM, Dale AM, Pripp AH, Vatnehol SAS, Emblem KE, Mardal KA, Eide PK (2018) Brain-wide glymphatic enhancement and clearance in humans assessed with MRI. JCI Insight 3. https://doi.org/10.1172/jci.insight.121537
**e L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, Donnell JO, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M (2013) Sleep drives metabolite clearance from the adult. Brain:373–378
Hablitz LM, Plá V, Giannetto M, Vinitsky HS, Stæger FF, Metcalfe T, Nguyen R, Benrais A, Nedergaard M (2020) Circadian control of brain glymphatic and lymphatic fluid flow. Nat Commun 11:4411. https://doi.org/10.1038/s41467-020-18115-2
Burfeind KG, Murchison CF, Westaway SK, Simon MJ, Erten-Lyons D, Kaye JA, Quinn JF, Iliff JJ (2017) The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer’s disease. Alzheimer’s & Dementia Transl Res Clin Interv 3:348. https://doi.org/10.1016/J.TRCI.2017.05.001
Zeppenfeld DM, Simon M, Haswell JD, D’Abreo D, Murchison C, Quinn JF, Grafe MR, Woltjer RL, Kaye J, Iliff JJ (2017) Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains. JAMA Neurol 74:91. https://doi.org/10.1001/jamaneurol.2016.4370
Xu Z, **ao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T, Hu G, **ao M (2015) Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener 10:58. https://doi.org/10.1186/s13024-015-0056-1
Abe Y, Ikegawa N, Yoshida K, Muramatsu K, Hattori S, Kawai K, Murakami M, Tanaka T, Goda W, Goto M, Yamamoto T, Hashimoto T, Yamada K, Shibata T, Misawa H, Mimura M, Tanaka KF, Miyakawa T, Iwatsubo T, Hata JI, Niikura T, Yasui M (2020) Behavioral and electrophysiological evidence for a neuroprotective role of aquaporin-4 in the 5xFAD transgenic mice model. Acta Neuropathol Commun 8:1–15. https://doi.org/10.1186/s40478-020-00936-3
Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, Binder LI, Mandelkow E-M, Diamond MI, Lee VM-Y, Holtzman DM (2011) In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human Tau transgenic mice. J Neurosci 31:13110–13117. https://doi.org/10.1523/JNEUROSCI.2569-11.2011
Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, Cirrito JR, Patel TK, Hochgräfe K, Mandelkow E-M, Holtzman DM (2014) Neuronal activity regulates extracellular tau in vivo. J Exp Med 211:387–393. https://doi.org/10.1084/jem.20131685
Frost B, Jacks RL, Diamond MI (2009) Propagation of Tau misfolding from the outside to the inside of a cell. J Biol Chem 284:12845–12852. https://doi.org/10.1074/jbc.M808759200
Kfoury N, Holmes BB, Jiang H, Holtzman DM, Diamond MI (2012) Trans-cellular propagation of Tau aggregation by fibrillar species. J Biol Chem 287:19440–19451. https://doi.org/10.1074/jbc.M112.346072
Barthélemy NR, Horie K, Sato C, Bateman RJ (2020) Blood plasma phosphorylated-Tau isoforms track CNS change in Alzheimer’s disease. J Exp Med 217:1–12. https://doi.org/10.1084/JEM.20200861
Yanamandra K, Patel TK, Jiang H, Schindler S, Ulrich JD, Boxer AL, Miller BL, Kerwin DR, Gallardo G, Stewart F, Finn MB, Cairns NJ, Verghese PB, Fogelman I, West T, Braunstein J, Robinson G, Keyser J, Roh J, Knapik SS, Hu Y, Holtzman DM (2017) Anti-tau antibody administration increases plasma Tau in transgenic mice and patients with tauopathy. Sci Transl Med 9. https://doi.org/10.1126/SCITRANSLMED.AAL2029
Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y, Yasui MI (2022) Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med 219. https://doi.org/10.1084/jem.20211275
Harrison IF, Ismail O, Machhada A, Colgan N, Ohene Y, Nahavandi P, Ahmed Z, Fisher A, Meftah S, Murray TK, Ottersen OP, Nagelhus EA, O’Neill MJ, Wells JA, Lythgoe MF (2020) Impaired glymphatic function and clearance of tau in an Alzheimer’s disease model. Brain 143:2576. https://doi.org/10.1093/brain/awaa179
Alshuhri MS, Gallagher L, Work LM, Holmes WM (2021) Direct imaging of glymphatic transport using H217O MRI. JCI Insight 6. https://doi.org/10.1172/jci.insight.141159
Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell Romie D, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560:185–191. https://doi.org/10.1038/s41586-018-0368-8
Tanaka Y, Yamada K, Satake K, Nishida I, Heuberger M, Kuwahara T, Iwatsubo T (2019) Seeding activity-based detection uncovers the different release mechanisms of seed-competent Tau versus inert Tau via lysosomal exocytosis. Front Neurosci 13:1–7. https://doi.org/10.3389/fnins.2019.01258
Aoyagi H, Hasegawa M, Tamaoka A (2007) Fibrillogenic nuclei composed of P301L mutant tau induce elongation of P301L tau but not wild-type tau. J Biol Chem 282:20309–20318. https://doi.org/10.1074/jbc.M611876200
Kress BT, Iliff JJ, **a M, Wang M, Wei Bs HS, Zeppenfeld D, **e L, Hongyi Kang BS, Xu Q, Liew JA, Plog BA, Ding F, PhD RD, Nedergaard M (2014) Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 76:845–861. https://doi.org/10.1002/ana.24271
Hablitz LM, Vinitsky HS, Sun Q, Stæger FF, Sigurdsson B, Mortensen KN, Lilius TO, Nedergaard M (2019) Increased glymphatic influx is correlated with high EEG delta power and low heart rate in mice under anesthesia. Sci Adv 5:eaav5447. https://doi.org/10.1126/sciadv.aav5447
Acknowledgments
This study was supported partially by JST CREST (Grant Number: JPMJCR18H3) (KY), the program for Brain Map** by Integrated Neurotechnologies for Disease Studies (Brain/MINDS) from Japan Agency for Medical Research and development, AMED (Grant Number: JP20dm0207073) (KY) and Grant-in-Aid for Scientific Research (C) (Grant Number:JP18K07388) (KY), the Collaborative Research Project (2021-20012)(2023-23012) of Brain Research Institute, Niigata University (KY), Grant-in-Aid for Scientific Research (B)(Grant Number:JP23H02792)(KY), NHMRC-AMED 2022 Dementia Collaborative Research Scheme from AMED (Grant Number: JP22jm0210103) (KY).
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Ishida, K., Yamada, K. (2024). Detection of Glymphatic Outflow of Tau from Brain to Cerebrospinal Fluid in Mice. In: Smet-Nocca, C. (eds) Tau Protein. Methods in Molecular Biology, vol 2754. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3629-9_19
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DOI: https://doi.org/10.1007/978-1-0716-3629-9_19
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