Skip to main content

A Method to Collect Cerebrospinal Fluid from Mouse Cisterna Magna to Determine Extracellular Tau Levels

  • Protocol
  • First Online:
Tau Protein

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2754))


Despite being a cytoplasmic protein abundant in neurons, tau is detectable in various extracellular fluids. In addition to being passively released from dying/degenerating neurons, tau is also actively released from living neurons in a neuronal activity-dependent mechanism. In vivo, tau released from neurons first appears in brain interstitial fluid (ISF) and subsequently drains into cerebrospinal fluid (CSF) by glymphatic system. Changes in CSF tau levels alter during the course of AD pathogenesis and are considered to predict the disease-progression of AD. A method to collect CSF from various mouse models of AD will serve as a valuable tool to investigate the dynamics of physiological/pathological tau released from neurons. In this chapter, we describe and characterize a method that reliably collects a relatively large volume of CSF from anesthetized mice.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions


  1. Plog BA, Nedergaard M (2018) The Glymphatic system in central nervous system health and disease: past, present, and future. Annu Rev Pathol Mech Dis 13:379–394.

    Article  CAS  Google Scholar 

  2. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, Sanders DW, Cook C, Fu H, Boonen RACM, Herman M, Nahmani E, Emrani S, Figueroa YH, Diamond MI, Clelland CL, Wray S, Duff KE (2016) Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci 19:1085–1092.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. 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.

  6. Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TLS, Buckles V, Fagan AM, Perrin RJ, Goate AM, Morris JC, Karch CM, Xiong C, Allegri R, Mendez PC, Berman SB, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Noble J, Farlow M, Chhatwal J, Graff-Radford NR, Salloway S, Schofield PR, Masters CL, Martins RN, O’Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E, Allegri R, Bateman R, Bechara J, Benzinger T, Berman S, Bodge C, Brandon S, Brooks W, Buck J, Buckles V, Chea S, Chhatwal J, Chrem Mendez P, Chui H, Cinco J, Clifford J, Cruchaga C, Donahue T, Douglas J, Edigo N, Erekin-Taner N, Fagan A, Farlow M, Fitzpatrick C, Flynn G, Fox N, Franklin E, Fujii H, Gant C, Gardener S, Ghetti B, Goate A, Goldman J, Gordon B, Graff-Radford N, Gray J, Groves A, Hassenstab J, Hoechst-Swisher L, Holtzman D, Hornbeck R, DiBari SH, Ikeuchi T, Ikonomovic S, Jerome G, Jucker M, Karch C, Kasuga K, Kawarabayashi T, Klunk W, Koeppe R, Kuder-Buletta E, Laske C, Lee JH, Levin J, Martins R, Mason NS, Masters C, Maue-Dreyfus D, McDade E, Mori H, Morris J, Nagamatsu A, Neimeyer K, Noble J, Norton J, Perrin R, Raichle M, Renton A, Ringman J, Roh JH, Salloway S, Schofield P, Shimada H, Sigurdson W, Sohrabi H, Sparks P, Suzuki K, Taddei K, Wang P, Xu X (2020) A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease. Nat Med 26:398–407.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Fagan AM, Xiong C, Jasielec MS, Bateman RJ, Goate AM, Benzinger TLS, Ghetti B, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Salloway S, Schofield PR, Sperling RA, Marcus D, Cairns NJ, Buckles VD, Ladenson JH, Morris JC, Holtzman DM (2014) Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer’s disease. Sci Transl Med 6:226ra30–226ra30.

    Article  CAS  Google Scholar 

  8. Sato C, Barthélemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, Sullivan M, Crisp MJ, Kasten T, Kirmess KM, Kanaan NM, Yarasheski KE, Baker-Nigh A, Benzinger TLS, Miller TM, Karch CM, Bateman RJ (2018) Tau kinetics in neurons and the human central nervous system. Neuron 97:1284–1298.e7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sankaranarayanan S, Barten DM, Vana L, Devidze N, Yang L, Cadelina G, Hoque N, DeCarr L, Keenan S, Lin A, Cao Y, Snyder B, Zhang B, Nitla M, Hirschfeld G, Barrezueta N, Polson C, Wes P, Rangan VS, Cacace A, Albright CF, Meredith J, Trojanowski JQ, Lee VMY, Brunden KR, Ahlijanian M (2015) Passive immunization with phospho-tau antibodies reduces tau pathology and functional deficits in two distinct mouse tauopathy models. PLoS One 10:1–28.

    Article  CAS  Google Scholar 

  10. Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P, Staufenbiel M, Jucker M (2013) Changes in amyloid-β and tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med 5:194re2–194re2.

    Article  CAS  Google Scholar 

  11. Kaeser SA, Häsler LM, Lambert M, Bergmann C, Bottelbergs A, Theunis C, Mercken M, Jucker M (2021) CSF p-tau increase in response to Aβ-type and Danish-type cerebral amyloidosis and in the absence of neurofibrillary tangles. Acta Neuropathol 143:287–290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schellea J, Häslera LM, Göpfertd JC, Joosd TO, Vanderstichelee H, Stoopse E, Mandelkow E-M, Neumanng U, Shimshekh DR, Staufenbiela M, Juckera M, Kaese SA (2017) Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement 13:701–709

    Article  Google Scholar 

  13. Simoes S, Neufeld JL, Triana-Baltzer G, Moughadam S, Chen EI, Kothiya M, Qureshi YH, Patel V, Honig LS, Kolb H, Small SA (2020) Tau and other proteins found in Alzheimer’s disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans. Sci Transl Med 12.

  14. Yamada K (2017) In vivo microdialysis of brain interstitial fluid for the determination of extracellular tau levels. In: Methods in molecular biology, Clifton, pp 285–296

    Google Scholar 

  15. Yamada K (2018) In vivo microdialysis method to collect large extracellular proteins from brain interstitial fluid with high-molecular weight cut-off probes. J Vis Exp 2018:1–6.

    Article  Google Scholar 

  16. 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.

  17. Planel E, Miyasaka T, Launey T, Chui DH, Tanemura K, Sato S, Murayama O, Ishiguro K, Tatebayashi Y, Takashima A (2004) Alterations in glucose metabolism induce hypothermia leading to tau hyperphosphorylation through differential inhibition of kinase and phosphatase activities: implications for Alzheimer’s disease. J Neurosci 24:2401–2411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Barkovits K, Kruse N, Linden A, Tönges L, Pfeiffer K, Mollenhauer B, Marcus K (2020) Blood contamination in CSF and its impact on quantitative analysis of alpha-synuclein. Cell 9.

  19. Barten DM, Cadelina GW, Hoque N, Decarr LB, Guss VL, Yang L, Sankaranarayanan S, Wes PD, Flynn ME, Meredith JE, Ahlijanian MK, Albright CF (2011) Tau transgenic mice as models for cerebrospinal fluid tau biomarkers. J Alzheimers Dis 24:127–141.

    Article  CAS  PubMed  Google Scholar 

  20. Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VMY (2007) Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53:337–351.

    Article  CAS  PubMed  Google Scholar 

  21. Yamada K, Patel TK, Hochgräfe K, Mahan TE, Jiang H, Stewart FR, Mandelkow E-M, Holtzman DM (2015) Analysis of in vivo turnover of tau in a mouse model of tauopathy. Mol Neurodegener 10:55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references


We thank Dr. Nakajima and Dr. Takeda at Osaka University for technical assistance during the development of this method. This study was supported partially by JST CREST (Grant Number: JPMJCR18H3) (KY), the program for Brain Mapping 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:18K07388) (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).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Kaoru Yamada .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2024 The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Ishida, K., Yamada, K. (2024). A Method to Collect Cerebrospinal Fluid from Mouse Cisterna Magna to Determine Extracellular Tau Levels. In: Smet-Nocca, C. (eds) Tau Protein. Methods in Molecular Biology, vol 2754. Humana, New York, NY.

Download citation

  • DOI:

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-3628-2

  • Online ISBN: 978-1-0716-3629-9

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics