Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y, Yasui M, Iwatsubo T. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med. 2022 Mar 7;219(3) Epub 2022 Feb 25 PubMed.

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  1. This paper reports that extracellular tau is cleared by the glymphatic system, and that loss of aquaporin 4 (AQP4)-driven fluid flow accelerates tau accumulation and neurodegeneration in a mouse model of tauopathy. In this elegant study, the authors replicate earlier findings from other groups using Aβ (Iliff et al., 2012; Xu et al., 2015) and demonstrate that AQP4-driven fluid flow through the brain is needed to wash out the brain parenchyma from waste products.

    The paper further suggests that proper fluid flow in the brain is needed for the draining function of the brain-covering, dural lymphatics that pick-up CSF and drain it into the deep cervical lymph nodes, thereby contributing to the removal of waste products from the brain (Louveau et al., 2015; Aspelund et al., 2015; Ahn et al., 2019). Ishida and colleagues nicely show that CSF-injected tau in AQP4 KO mice is retained in the CSF, does not reach the deep cervical lymph nodes, and is not influxed as efficiently into the brain parenchyma as it is in wild-type mice.

    The glymphatic system is compromised in the awake state, in aging, and after brain injuries such as ischemic stroke or subarachnoid hemorrhage (Gaberel et al., 2014), which are all known risk factors for Alzheimer’s disease and other dementias. Interestingly, glymphatic perfusion after subarachnoid hemorrhage could be improved by intracerebroventricular injection of tissue-type plasminogen activator (Gaberel et al., 2014), which suggests that the system is targetable. Future research is needed to find out if, and how, we can employ these routes to enhance brain perfusion and prevent the accumulation of neurotoxic waste in proteinopathies as seen in many neurodegenerative diseases.

    The glymphatic system is not alone in mediating brain clearance. AQP4-driven fluid flow through the brain is required for the distribution of extracellular solutes throughout the brain and into the CSF space, and the cells in the brain parenchyma, blood vessels, and dural lymphatics subsequently eliminate waste proteins.

    References:

    Ahn JH, Cho H, Kim JH, Kim SH, Ham JS, Park I, Suh SH, Hong SP, Song JH, Hong YK, Jeong Y, Park SH, Koh GY. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature. 2019 Jul 24; PubMed.

    Aspelund A, Antila S, Proulx ST, Karlsen TV, Karaman S, Detmar M, Wiig H, Alitalo K. A dural lymphatic vascular system that drains brain interstitial fluid and macromolecules. J Exp Med. 2015 Jun 29;212(7):991-9. Epub 2015 Jun 15 PubMed.

    Gaberel T, Gakuba C, Goulay R, Martinez De Lizarrondo S, Hanouz JL, Emery E, Touze E, Vivien D, Gauberti M. Impaired glymphatic perfusion after strokes revealed by contrast-enhanced MRI: a new target for fibrinolysis?. Stroke. 2014 Oct;45(10):3092-6. Epub 2014 Sep 4 PubMed.

    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012 Aug 15;4(147):147ra111. PubMed.

    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. Epub 2015 Jun 1 PubMed.

    Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T, Hu G, Xiao M. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener. 2015 Nov 2;10:58. PubMed.

    View all comments by Steffen Storck

  2. This study by Ishida et al. corroborates the important role of the brain perivascular routes, known as the glymphatic system (Iliff et al., 2012; Xie et al., 2013), for the clearance of extracellular tau. As others have shown in the past, defects in aquaporin 4 (AQP4) lead to impaired glymphatic function, and to the retainment of toxic extracellular molecules in the brain’s interstitium, such as the aggregation-prone Aβ (Peng et al., 2016; Xu et al., 2015). In this new study, Ishida et al. show that the same applies to extracellular tau. The present study also shows that deficiency in AQP4 aggravates tau hyperphosphorylation and neurodegeneration in a model of tauopathy.

    I find it very interesting that the authors show that drainage of tau from the cerebrospinal fluid into the deep cervical lymph nodes is severely compromised in mice that lack AQP4. This is somewhat puzzling, because the process of CSF drainage into the deep cervical lymph nodes is solely mediated by the lymphatic vasculature, namely the meningeal lymphatics (Louveau et al., 2015; das Neves et al., 2021). It was recently shown that reduced meningeal lymphatic drainage might also contribute to defects in perivascular circulation of CSF through the glymphatic system, and to the buildup of Aβ plaques in the brain (Da Mesquita et al., 2018; Da Mesquita et al., 2021). Moreover, mice that lack a meningeal lymphatic vascular system also present decreased drainage of tau from the brain into the deep cervical lymph nodes (Patel et al., 2019). 

    Taking into consideration that the authors used a constitutive Aqp4-/- mouse line, it will be important to investigate whether there are defects in meningeal lymphatic vasculature in this Aqp4-/- mouse model, developmental or otherwise, that might explain such outcomes.

    It will also be essential to understand whether the clearance of extracellular Aβ or tau in Aqp4-/- mice, which present constitutive defects in glymphatics, can be therapeutically boosted by treating mice with the pro-lymphangiogenic vascular endothelial growth factor C, which acts primarily on the meningeal lymphatic vessels draining the central nervous system.

    Overall, this is very interesting work that broadens our understanding about the importance of the glymphatic and lymphatic systems for extracellular tau clearance from the brain and might prove to be of great therapeutic relevance for Alzheimer’s disease, frontotemporal dementia, and other neurodegenerative disorders afflicted by evident brain tauopathy.

    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. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012 Aug 15;4(147):147ra111. PubMed.

    Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O'Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, Nedergaard M. Sleep drives metabolite clearance from the adult brain. Science. 2013 Oct 18;342(6156):373-7. PubMed.

    Peng W, Achariyar TM, Li B, Liao Y, Mestre H, Hitomi E, Regan S, Kasper T, Peng S, Ding F, Benveniste H, Nedergaard M, Deane R. Suppression of glymphatic fluid transport in a mouse model of Alzheimer's disease. Neurobiol Dis. 2016 Sep;93:215-25. Epub 2016 May 24 PubMed.

    Xu Z, Xiao N, Chen Y, Huang H, Marshall C, Gao J, Cai Z, Wu T, Hu G, Xiao M. Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits. Mol Neurodegener. 2015 Nov 2;10:58. PubMed.

    Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015 Jul 16;523(7560):337-41. Epub 2015 Jun 1 PubMed.

    das Neves SP, Delivanoglou N, Da Mesquita S. CNS-Draining Meningeal Lymphatic Vasculature: Roles, Conundrums and Future Challenges. Front Pharmacol. 2021;12:655052. Epub 2021 Apr 28 PubMed.

    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 RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J. Functional aspects of meningeal lymphatics in ageing and Alzheimer's disease. Nature. 2018 Aug;560(7717):185-191. Epub 2018 Jul 25 PubMed.

    Da Mesquita S, Papadopoulos Z, Dykstra T, Brase L, Farias FG, Wall M, Jiang H, Kodira CD, de Lima KA, Herz J, Louveau A, Goldman DH, Salvador AF, Onengut-Gumuscu S, Farber E, Dabhi N, Kennedy T, Milam MG, Baker W, Smirnov I, Rich SS, Dominantly Inherited Alzheimer Network, Benitez BA, Karch CM, Perrin RJ, Farlow M, Chhatwal JP, Holtzman DM, Cruchaga C, Harari O, Kipnis J. Meningeal lymphatics affect microglia responses and anti-Aβ immunotherapy. Nature. 2021 May;593(7858):255-260. Epub 2021 Apr 28 PubMed.

    Patel TK, Habimana-Griffin L, Gao X, Xu B, Achilefu S, Alitalo K, McKee CA, Sheehan PW, Musiek ES, Xiong C, Coble D, Holtzman DM. Dural lymphatics regulate clearance of extracellular tau from the CNS. Mol Neurodegener. 2019 Feb 27;14(1):11. PubMed.

    View all comments by Sandro Da Mesquita

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