Skip to main content

Microglial Uptake of Extracellular Tau by Actin-Mediated Phagocytosis

  • Protocol
  • First Online:
Neuroprotection

Abstract

Microglia are scavengers of the brain environment that clear dead cells, debris, and microbes. In Alzheimer’s disease, microglia get activated to phagocytose damaged neurons, extracellular Amyoid-β, and Tau deposits. Several Tau internalization mechanisms of microglia have been studied which include phagocytosis, pinocytosis, and receptor-mediated endocytosis. In this chapter, we have visualized microglial phagocytic structures that are actin-rich cup-like extensions, which surrounds extracellular Tau species by wide-field fluorescence and confocal microscopy. We have shown the association of filamentous actin in Tau phagocytosis along the assembly of LC-3 molecules to phagosomes. The 3-dimensional, orthogonal and gallery wise representation of these phagocytic structures provides an overview of the phagocytic mechanism of extracellular Tau by microglia.

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

Access this chapter

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 279.99
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

Similar content being viewed by others

References

  1. Cowan M, Petri WA Jr (2018) Microglia: immune regulators of neurodevelopment. Front Immunol 9:2576

    Article  PubMed  PubMed Central  Google Scholar 

  2. Franco-Bocanegra DK, McAuley C, Nicoll JA, Boche D (2019) Molecular mechanisms of microglial motility: changes in ageing and Alzheimer’s disease. Cell 8(6):639

    Article  CAS  Google Scholar 

  3. Bilbo SD, Schwarz JM (2012) The immune system and developmental programming of brain and behavior. Front Neuroendocrinol 33(3):267–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Binder LI, Frankfurter A, Rebhun LI (1985) The distribution of tau in the mammalian central nervous system. J Cell Biol 101(4):1371–1378

    Article  CAS  PubMed  Google Scholar 

  5. Conde C, Cáceres A (2009) Microtubule assembly, organization and dynamics in axons and dendrites. Nat Rev Neurosci 10(5):319–332

    Article  CAS  PubMed  Google Scholar 

  6. Gong C-X, Liu F, Grundke-Iqbal I, Iqbal K (2005) Post-translational modifications of tau protein in Alzheimer’s disease. J Neural Transm 112(6):813–838

    Article  CAS  PubMed  Google Scholar 

  7. Martin L, Latypova X, Terro F (2011) Post-translational modifications of tau protein: implications for Alzheimer’s disease. Neurochem Int 58(4):458–471

    Article  CAS  PubMed  Google Scholar 

  8. Sonawane SK, Chinnathambi S (2018) Prion-like propagation of post-translationally modified tau in Alzheimer’s disease: a hypothesis. J Mol Neurosci 65(4):480–490

    Article  CAS  PubMed  Google Scholar 

  9. Sonawane SK, Dubey T, Balmik AA, Das R, Chinnathambi S (2021) Alzheimer’s disease pathology: a tau perspective. In: Govindaraju T (ed) Alzheimer’s disease: recent findings in pathophysiology, diagnostic and therapeutic modalities. The Royal Society of Chemistry

    Google Scholar 

  10. Das R, Chinnathambi S (2019) Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease. Cell Mol Life Sci 76(19):3681–3694

    Article  CAS  PubMed  Google Scholar 

  11. Balmik AA, Das R, Dangi A, Gorantla NV, Marelli UK, Chinnathambi S (2020) Melatonin interacts with repeat domain of tau to mediate disaggregation of paired helical filaments. Biochim Biophys Acta Gen Subj 1864(3):129467

    Article  CAS  PubMed  Google Scholar 

  12. Das R, Balmik AA, Chinnathambi S (2020) Effect of melatonin on tau aggregation and tau-mediated cell surface morphology. Int J Biol Macromol 152:30–39

    Article  CAS  PubMed  Google Scholar 

  13. Gorantla NV, Das R, Chidambaram H, Dubey T, Mulani FA, Thulasiram HV, Chinnathambi S (2020) Basic limonoid modulates chaperone-mediated proteostasis and dissolve tau fibrils. Sci Rep 10(1):4023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Gorantla NV, Landge VG, Nagaraju PG, Priyadarshini CGP, Balaraman E, Chinnathambi S (2019) Molecular cobalt (II) complexes for tau polymerization in Alzheimer’s disease. ACS Omega 4(16):16702–16714

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sonawane SK, Ahmad A, Chinnathambi S (2019) Protein-capped metal nanoparticles inhibit tau aggregation in Alzheimer’s disease. ACS Omega 4(7):12833–12840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sonawane SK, Balmik AA, Boral D, Ramasamy S, Chinnathambi S (2019) Baicalein suppresses repeat tau fibrillization by sequestering oligomers. Arch Biochem Biophys 675:108119

    Article  CAS  PubMed  Google Scholar 

  17. Sonawane SK, Chidambaram H, Boral D, Gorantla NV, Balmik AA, Dangi A, Ramasamy S, Marelli UK, Chinnathambi S (2020) EGCG impedes human tau aggregation and interacts with tau. Sci Rep 10(1):12579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sonawane SK, Chinnathambi S (2021) Epigallocatechin-3-gallate modulates tau post-translational modifications and cytoskeletal network. Oncotarget 12(11):1083

    Article  PubMed  PubMed Central  Google Scholar 

  19. Chidambaram H, Das R, Chinnathambi S (2022) G-protein coupled purinergic P2Y12 receptor interacts and internalizes TauRD-mediated by membrane-associated actin cytoskeleton remodelling in microglia. Eur J Cell Biol:151201

    Google Scholar 

  20. Das R, Balmik AA, Chinnathambi S (2020) Phagocytosis of full-length tau oligomers by actin-remodeling of activated microglia. J Neuroinflammation 17(1):1–15

    Article  Google Scholar 

  21. Das R, Chinnathambi S (2021) Microglial remodeling of actin network by tau oligomers, via G protein-coupled purinergic receptor, P2Y12R-driven chemotaxis. Traffic 22(5):153–170

    Article  CAS  PubMed  Google Scholar 

  22. Desale SE, Chinnathambi S (2021) α–Linolenic acid modulates phagocytosis and endosomal pathways of extracellular tau in microglia. Cell Adhes Migr 15(1):84–100

    Article  CAS  Google Scholar 

  23. Kolay S, Vega AR, Dodd DA, Perez VA, Kashmer OM, White CL, Diamond MI (2022) The dual fates of exogenous tau seeds: lysosomal clearance versus cytoplasmic amplification. J Biol Chem 298(6)

    Google Scholar 

  24. Perea JR, López E, Díez-Ballesteros JC, Ávila J, Hernández F, Bolós M (2019) Extracellular monomeric tau is internalized by astrocytes. Front Neurosci 13:442

    Article  PubMed  PubMed Central  Google Scholar 

  25. Evans LD, Wassmer T, Fraser G, Smith J, Perkinton M, Billinton A, Livesey FJ (2018) Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways. Cell Rep 22(13):3612–3624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bolós M, Llorens-Martín M, Perea JR, Jurado-Arjona J, Rábano A, Hernández F, Avila J (2017) Absence of CX3CR1 impairs the internalization of tau by microglia. Mol Neurodegener 12(1):59

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chidambaram H, Das R, Chinnathambi S (2020) Interaction of tau with the chemokine receptor, CX3CR1 and its effect on microglial activation, migration and proliferation. Cell Biosci 10(1):1–9

    Article  Google Scholar 

  28. Pelucchi S, Stringhi R, Marcello E (2020) Dendritic spines in Alzheimer’s disease: how the actin cytoskeleton contributes to synaptic failure. Int J Mol Sci 21(3):908

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bosch M, Castro J, Saneyoshi T, Matsuno H, Sur M, Hayashi Y (2014) Structural and molecular remodeling of dendritic spine substructures during long-term potentiation. Neuron 82(2):444–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jones B (2013) TREM2 linked to late-onset AD. Nat Rev Neurol 9(1):5–5

    Article  PubMed  Google Scholar 

  31. Zhao Y, Wu X, Li X, Jiang L-L, Gui X, Liu Y, Sun Y, Zhu B, Piña-Crespo JC, Zhang M (2018) TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97(5):1023–1031.e1027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446(7139):1091–1095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hanke ML, Kielian T (2011) Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci 121(9):367–387

    Article  CAS  Google Scholar 

  34. Ribes S, Ebert S, Regen T, Czesnik D, Scheffel J, Zeug A, Bunkowski S, Eiffert H, Hanisch UK, Hammerschmidt S (2010) Fibronectin stimulates Escherichia coli phagocytosis by microglial cells. Glia 58(3):367–376

    Article  PubMed  Google Scholar 

  35. Song M, Jin J, Lim J, Kou J, Pattanayak A, Rehman J, Kim H, Tahara K, Lalonde R, Fukuchi K (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8:92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Rava A, La Rosa P, Palladino G, Dragotto J, Totaro A, Tiberi J, Canterini S, Oddi S, Fiorenza MT (2022) The appearance of phagocytic microglia in the postnatal brain of Niemann Pick type C mice is developmentally regulated and underscores shortfalls in fine odor discrimination. J Cell Physiol 237(12):4563–4579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. VanRyzin JW, Marquardt AE, Argue KJ, Vecchiarelli HA, Ashton SE, Arambula SE, Hill MN, McCarthy MM (2019) Microglial phagocytosis of newborn cells is induced by endocannabinoids and sculpts sex differences in juvenile rat social play. Neuron 102(2):435–449.e436

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chidambaram H, Chinnathambi S (2020) Role of cysteines in accelerating tau filament formation. J Biomol Struct Dyn:1–10

    Google Scholar 

Download references

Acknowledgments

The author is grateful to Chinnathambi’s lab members for their scientific suggestions on the manuscript. CHK, SD, and TQ acknowledges the Department of Science and Technology, Department of Biotechnology, and Government of India for the fellowship. The authors acknowledge the Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences (NIMHANS), and the Institute of National Importance, Bengaluru, for their internal support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Subashchandrabose Chinnathambi .

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

Chidambaram, H., Desale, S.E., Qureshi, T., Chinnathambi, S. (2024). Microglial Uptake of Extracellular Tau by Actin-Mediated Phagocytosis. In: Ray, S.K. (eds) Neuroprotection. Methods in Molecular Biology, vol 2761. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-3662-6_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-3662-6_16

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-3661-9

  • Online ISBN: 978-1-0716-3662-6

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics