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Tau uptake by human neurons depends on receptor LRP1 and kinase LRRK2

Evans, Lewis D, Strano, Alessio, Tuck, Eleanor, Campbell, Ashley, Smith, James, Hung, Christy, Behr, Tiana S, Ghetti, Bernardino, Ryskeldi-Falcon, Benjamin, Karakoc, Emre, Iorio, Francesco, Reith, Alastair, Bassett, Andrew R, Livesey, Frederick J·2025·The EMBO Journal
DOI 10.1038/s44318-025-00514-0PMC PMC12436637
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Abstract

Extracellular release and uptake of pathogenic forms of the microtubule-associated protein tau contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease. Defining the cellular mechanisms and pathways for tau entry to human neurons is essential to understanding tauopathy pathogenesis and enabling the rational design of disease-modifying therapeutics. Here, whole-genome, loss-of-function CRISPR screens in human iPSC-derived excitatory neurons, the major neuronal cell type affected in these diseases, provide insights into the different cellular pathways for uptake of extracellular monomeric and fibrillar tau. Monomeric and fibrillar tau are both taken up by human neurons by receptor-mediated endocytosis, but involve different routes of entry at the neuronal surface: the low-density lipoprotein LRP1 is the primary receptor for monomeric tau, but contributes less to fibrillar tau entry. Similarly, endocytosis of monomeric tau is dependent on the familial Parkinson’s disease gene LRRK2, but not required for endocytosis of fibrillar tau. These findings implicate LRP1 and LRRK2 in the pathogenesis of tauopathies and Parkinson’s disease, and identify LRRK2 as a potential therapeutic target for altering progression of these diseases.

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Crossref · 10.1038/s44318-025-00514-0

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  • LRP1 has been implicated in the uptake and degradation of amyloid-β and tau.

    “which has been implicated in the uptake and degradation of amyloid-β and tau [107, 147].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [147]

    The Results section on the CRISPR screens identifies LRP1 as a major receptor for neuronal uptake of monomeric tau, but not fibrillar tau (page unavailable). The Results section on LRRK2 measures amyloid-β uptake without attributing it to LRP1, and the Introduction says the uptake assays limited the relevance of tau degradation. Our copy therefore does not support the claims about LRP1-mediated amyloid-β uptake or degradation of either protein. (LLM, conf=0.88)

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Research works printed but not linked: 59

  1. Aranda B, Blankenburg H, Kerrien S, Brinkman FSL, Ceol A, Chautard E, Dana JM, De Las Rivas J, Dumousseau M, Galeota E et al (2011) PSICQUIC and PSISCORE: accessing and scoring molecular interactions. Nat Methods 8:528–529 · DOI
  2. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, Wolozin B, Butovsky O, Kügler S, Ikezu T (2015) Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci 18:1584–1593 · DOI · Paper page
  3. Bilanges B, Posor Y, Vanhaesebroeck B (2019) PI3K isoforms in cell signalling and vesicle trafficking. Nat Rev Mol Cell Biol 20:515–534 · DOI
  4. Binder JX, Pletscher-Frankild S, Tsafou K, Stolte C, O’Donoghue SI, Schneider R, Jensen LJ (2014) COMPARTMENTS: unification and visualization of protein subcellular localization evidence. Database 2014:bau012 · DOI
  5. Bowman EJ, Siebers A, Altendorf K (1988) Bafilomycins: a class of inhibitors of membrane ATPases from microorganisms, animal cells, and plant cells. Proc Natl Acad Sci USA 85:7972–7976 · DOI
  6. Bruntraeger M, Byrne M, Long K, Bassett AR (2019) Editing the genome of human induced pluripotent stem cells using CRISPR/Cas9 ribonucleoprotein complexes. Methods Mol Biol 1961:153–183 · DOI
  7. Collinet C, Stöter M, Bradshaw CR, Samusik N, Rink JC, Kenski D, Habermann B, Buchholz F, Henschel R, Mueller MS et al (2010) Systems survey of endocytosis by multiparametric image analysis. Nature 464:243–249 · DOI
  8. Collins MP, Forgac M (2020) Regulation and function of V-ATPases in physiology and disease. Biochim Biophys Acta Biomembr 1862:183341 · DOI
  9. Cuenda A, Alessi DR (2000) Use of kinase inhibitors to dissect signaling pathways. Methods Mol Biol 99:161–175
  10. Cullen PJ, Steinberg F (2018) To degrade or not to degrade: mechanisms and significance of endocytic recycling. Nat Rev Mol Cell Biol 19:679–696 · DOI · Paper page
  11. Daniloski Z, Jordan TX, Wessels H-H, Hoagland DA, Kasela S, Legut M, Maniatis S, Mimitou EP, Lu L, Geller E et al (2021) Identification of required host factors for SARS-CoV-2 infection in human cells. Cell 184:92–105.e16 · DOI
  12. D’Souza Z, Taher FS, Lupashin VV (2020) Golgi inCOGnito: from vesicle tethering to human disease. Biochim Biophys Acta Gen Subj 1864:129694 · DOI
  13. 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 22:3612–3624 · DOI
  14. Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SHW, Goedert M (2018) Tau filaments from multiple cases of sporadic and inherited Alzheimer’s disease adopt a common fold. Acta Neuropathol 136:699–708 · DOI · Paper page
  15. Fell MJ, Mirescu C, Basu K, Cheewatrakoolpong B, DeMong DE, Ellis JM, Hyde LA, Lin Y, Markgraf CG, Mei H et al (2015) MLi-2, a potent, selective, and centrally active compound for exploring the therapeutic potential and safety of LRRK2 kinase inhibition. J Pharmacol Exp Ther 355:397–409 · DOI
  16. Flint M, Chatterjee P, Lin DL, McMullan LK, Shrivastava-Ranjan P, Bergeron É, Lo MK, Welch SR, Nichol ST, Tai AW et al (2019) A genome-wide CRISPR screen identifies N-acetylglucosamine-1-phosphate transferase as a potential antiviral target for Ebola virus. Nat Commun 10:285 · DOI
  17. Gilks WP, Abou-Sleiman PM, Gandhi S, Jain S, Singleton A, Lees AJ, Shaw K, Bhatia KP, Bonifati V, Quinn NP et al (2005) A common LRRK2 mutation in idiopathic Parkinson’s disease. Lancet 365:415–416
  18. Goedert M, Eisenberg DS, Crowther RA (2017) Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40:189–210 · DOI · Paper page
  19. Hardy J (2010) Genetic analysis of pathways to Parkinson disease. Neuron 68:201–206 · DOI
  20. Heaton GR, Landeck N, Mamais A, Nalls MA, Nixon-Abell J, Kumaran R, Beilina A, Pellegrini L, Li Y, International Parkinson Disease Genomics Consortium (IPDGC). et al (2020) Sequential screening nominates the Parkinson’s disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis. Neurobiol Dis 141:104948 · DOI · Paper page
  21. Henderson MX, Sengupta M, Trojanowski JQ, VMY Lee (2019) Alzheimer’s disease tau is a prominent pathology in LRRK2 Parkinson’s disease. Acta Neuropathol Commun 7:183 · DOI
  22. Herz J, Goldstein JL, Strickland DK, Ho YK, Brown MS (1991) 39-kDa protein modulates binding of ligands to low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor. J Biol Chem 266:21232–21238 · DOI · Paper page
  23. Hill KJ, Stevens TH (1994) Vma21p is a yeast membrane protein retained in the endoplasmic reticulum by a di-lysine motif and is required for the assembly of the vacuolar H(+)-ATPase complex. Mol Biol Cell 5:1039–1050 · DOI
  24. Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Belaygorod L, Cairns NJ, Holtzman DM, Diamond MI (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci USA 111:E4376–E4385
  25. Hoshi T, Tezuka T, Yokoyama K, Iemura S, Natsume T, Yamanashi Y (2013) Mesdc2 plays a key role in cell-surface expression of Lrp4 and postsynaptic specialization in myotubes. FEBS Lett 587:3749–3754 · DOI
  26. Jabbari E, Koga S, Valentino RR, Reynolds RH, Ferrari R, Tan MMX, Rowe JB, Dalgard CL, Scholz SW, Dickson DW et al (2021) Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol 20:107–116 · DOI · Paper page
  27. Kaniyappan S, Tepper K, Biernat J, Chandupatla RR, Hübschmann S, Irsen S, Bicher S, Klatt C, Mandelkow E-M, Mandelkow E (2020) FRET-based Tau seeding assay does not represent prion-like templated assembly of Tau fibers. Mol Neurodegeneration 15:39 · DOI
  28. Kozik P, Hodson NA, Sahlender DA, Simecek N, Soromani C, Wu J, Collinson LM, Robinson MS (2013) A human genome-wide screen for regulators of clathrin-coated vesicle formation reveals an unexpected role for the V-ATPase. Nat Cell Biol 15:50–60 · DOI
  29. Lee VM-Y, Goedert M, Trojanowski JQ (2001) Neurodegenerative tauopathies. Ann Rev Neurosci 24:1121–1159 · DOI · Paper page
  30. Li B, Clohisey SM, Chia BS, Wang B, Cui A, Eisenhaure T, Schweitzer LD, Hoover P, Parkinson NJ, Nachshon A et al (2020) Genome-wide CRISPR screen identifies host dependency factors for influenza A virus infection. Nat Commun 11:164
  31. Li W, Xu H, Xiao T, Cong L, Love MI, Zhang F, Irizarry RA, Liu JS, Brown M, Liu XS (2014) MAGeCK enables robust identification of essential genes from genome-scale CRISPR/Cas9 knockout screens. Genome Biol 15:554
  32. Li Y, Muffat J, Omer Javed A, Keys HR, Lungjangwa T, Bosch I, Khan M, Virgilio MC, Gehrke L, Sabatini DM et al (2019) Genome-wide CRISPR screen for Zika virus resistance in human neural cells. Proc Natl Acad Sci USA 116:9527–9532 · DOI
  33. Liu Q, Bautista-Gomez J, Higgins DA, Yu J, Xiong Y (2021) Dysregulation of the AP2M1 phosphorylation cycle by LRRK2 impairs endocytosis and leads to dopaminergic neurodegeneration. Sci Signal 14:eabg3555 · DOI
  34. McEwan WA, Falcon B, Vaysburd M, Clift D, Oblak AL, Ghetti B, Goedert M, James LC (2017) Cytosolic Fc receptor TRIM21 inhibits seeded tau aggregation. Proc Natl Acad Sci USA 114:574–579 · DOI · Paper page
  35. Moore S, Evans LDB, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K et al (2015) APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep 11:689–696 · DOI · Paper page
  36. Pellegrini L, Hauser DN, Li Y, Mamais A, Beilina A, Kumaran R, Wetzel A, Nixon-Abell J, Heaton G, Rudenko I et al (2018) Proteomic analysis reveals co-ordinated alterations in protein synthesis and degradation pathways in LRRK2 knockout mice. Hum Mol Genet 27:3257–3271 · DOI
  37. Poulopoulos M, Cortes E, Vonsattel J-PG, Fahn S, Waters C, Cote LJ, Moskowitz C, Honig LS, Clark LN, Marder KS et al (2012) Clinical and pathological characteristics of LRRK2 G2019S patients with PD. J Mol Neurosci 47:139–143 · DOI
  38. Raiborg C, Stenmark H (2009) The ESCRT machinery in endosomal sorting of ubiquitylated membrane proteins. Nature 458:445–452 · DOI · Paper page
  39. Rajput A, Dickson DW, Robinson CA, Ross OA, Dächsel JC, Lincoln SJ, Cobb SA, Rajput ML, Farrer MJ (2006) Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 67:1506–1508 · DOI
  40. Rauch JN, Chen JJ, Sorum AW, Miller GM, Sharf T, See SK, Hsieh-Wilson LC, Kampmann M, Kosik KS (2018) Tau internalization is regulated by 6-O sulfation on heparan sulfate proteoglycans (HSPGs). Sci Rep 8:6382 · DOI · Paper page
  41. Raudvere U, Kolberg L, Kuzmin I, Arak T, Adler P, Peterson H, Vilo J (2019) g:Profiler: a web server for functional enrichment analysis and conversions of gene lists (2019 update). Nucleic Acids Res 47:W191–W198 · DOI · Paper page
  42. Renard D (2011) Roger S. Bivand, Edzer J. Pebesma, Virgilio Gomez-Rubio: applied spatial data analysis with R. Math Geosci 43:607–609 · DOI
  43. Ricci Hagman J, Westman JS, Hellberg Å, Olsson ML (2018) An update on the GLOB blood group system (and former GLOB collection). Immunohematology 34:161–163 · DOI
  44. Roosen DA, Cookson MR (2016) LRRK2 at the interface of autophagosomes, endosomes and lysosomes. Mol Neurodegener 11:73 · DOI
  45. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B et al (2012) Fiji: an open-source platform for biological-image analysis. Nat Methods 9:676–682 · DOI · Paper page
  46. Shi Y, Kirwan P, Livesey FJ (2012a) Directed differentiation of human pluripotent stem cells to cerebral cortex neurons and neural networks. Nat Protoc 7:1836–1846 · DOI · Paper page
  47. Shi Y, Kirwan P, Smith J, Robinson HPC, Livesey FJ (2012b) Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat Neurosci 15:477–486. S1 · DOI · Paper page
  48. Singh F, Prescott AR, Rosewell P, Ball G, Reith AD, Ganley IG (2021) Pharmacological rescue of impaired mitophagy in Parkinson’s disease-related LRRK2 G2019S knock-in mice. Elife 10:e67604
  49. Slaymaker IM, Gao L, Zetsche B, Scott DA, Yan WX, Zhang F (2016) Rationally engineered Cas9 nucleases with improved specificity. Science 351:84–88 · DOI · Paper page
  50. Strano A, Tuck E, Stubbs VE, Livesey FJ (2020) Variable outcomes in neural differentiation of human PSCs arise from intrinsic differences in developmental signaling pathways. Cell Rep 31:107732 · DOI
  51. Tasegian A, Singh F, Ganley IG, Reith AD, Alessi DR (2021) Impact of Type II LRRK2 inhibitors on signaling and mitophagy. Biochem J 478:3555–3573 · DOI
  52. Taylor M, Alessi DR (2020) Advances in elucidating the function of leucine-rich repeat protein kinase-2 in normal cells and Parkinson’s disease. Curr Opin Cell Biol 63:102–113 · DOI · Paper page
  53. Thorley JA, McKeating JA, Rappoport JZ (2010) Mechanisms of viral entry: sneaking in the front door. Protoplasma 244:15 · DOI
  54. Tzelepis K, Koike-Yusa H, De Braekeleer E, Li Y, Metzakopian E, Dovey OM, Mupo A, Grinkevich V, Li M, Mazan M et al (2016) A CRISPR dropout screen identifies genetic vulnerabilities and therapeutic targets in acute myeloid leukemia. Cell Rep 17:1193–1205 · DOI · Paper page
  55. Vogel JW, Iturria-Medina Y, Strandberg OT, Smith R, Levitis E, Evans AC, Hansson O (2020) Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease. Nat Commun 11:2612
  56. Walsh DM, Selkoe DJ (2016) A critical appraisal of the pathogenic protein spread hypothesis of neurodegeneration. Nat Rev Neurosci 17:251–260 · DOI
  57. Wang H, Yang J, Schneider JA, De Jager PL, Bennett DA, Zhang H-Y (2020) Genome-wide interaction analysis of pathological hallmarks in Alzheimer’s disease. Neurobiol Aging 93:61–68 · DOI
  58. Wang T, Wei JJ, Sabatini DM, Lander ES (2014) Genetic screens in human cells using the CRISPR-Cas9 system. Science 343:80–84 · DOI · Paper page
  59. West AB, Moore DJ, Biskup S, Bugayenko A, Smith WW, Ross CA, Dawson VL, Dawson TM (2005) Parkinson’s disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity. Proc Natl Acad Sci USA 102:16842–16847 · DOI · Paper page

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Metadata

Authors
Evans, L. D., Strano, A., Tuck, E., Campbell, A., Smith, J., Hung, C., Behr, T. S., Ghetti, B., Ryskeldi-Falcon, B., Karakoc, E., Iorio, F., Reith, A., Bassett, A. R., & Livesey, F. J.
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2025-08-11
Volume
44
Issue
18
ISSN
  • 0261-4189
  • 1460-2075
DOI
10.1038/s44318-025-00514-0
PMC
PMC12436637
Cited by
16
References
14
Language
en
Licence
Funders
  • OpenTargets (OTAR036)
  • Alzheimer's Research UK (Stem Cell Research Centre)
  • Wellcome Trust (WT101052MA)
  • Great Ormond Street Hospital Charity (Stem Cell Professorship)
  • NIHR | NIHR Great Ormond Street Hospital Biomedical Research Centre (N/A)

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