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LRP1 is a master regulator of tau uptake and spread

Nature volume 580, pages 381–385 (2020)Cite this article

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Abstract

The spread of protein aggregates during disease progression is a common theme underlying many neurodegenerative diseases. The microtubule-associated protein tau has a central role in the pathogenesis of several forms of dementia known as tauopathies—including Alzheimer’s disease, frontotemporal dementia and chronic traumatic encephalopathy1. Progression of these diseases is characterized by the sequential spread and deposition of protein aggregates in a predictable pattern that correlates with clinical severity2. This observation and complementary experimental studies3,4 have suggested that tau can spread in a prion-like manner, by passing to naive cells in which it templates misfolding and aggregation. However, although the propagation of tau has been extensively studied, the underlying cellular mechanisms remain poorly understood. Here we show that the low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis of tau and its subsequent spread. Knockdown of LRP1 significantly reduced tau uptake in H4 neuroglioma cells and in induced pluripotent stem cell-derived neurons. The interaction between tau and LRP1 is mediated by lysine residues in the microtubule-binding repeat region of tau. Furthermore, downregulation of LRP1 in an in vivo mouse model of tau spread was found to effectively reduce the propagation of tau between neurons. Our results identify LRP1 as a key regulator of tau spread in the brain, and therefore a potential target for the treatment of diseases that involve tau spread and aggregation.

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Fig. 1: Tau uptake is mediated by LRP1.
Fig. 2: Tau interacts with LRP1 in a similar manner to known ligands.
Fig. 3: LRP1 mediates tau uptake in neurons.
Fig. 4: LRP1 knockdown reduces tau spread in vivo.

Data availability

Source data are available for graphs plotted in Figs. 1–4 and Extended Data Figs. 1–3. Scans of the full western blot gels can be found in Supplementary Fig. 1. All other data are available from the corresponding author upon reasonable request.

References

  1. Goedert, M., Eisenberg, D. S. & Crowther, R. A. Propagation of tau aggregates and neurodegeneration. Annu. Rev. Neurosci. 40, 189–210 (2017).

    Article  CAS  Google Scholar 

  2. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).

    Article  CAS  Google Scholar 

  3. de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).

    Article  Google Scholar 

  4. Guo, J. L. et al. Unique pathological tau conformers from Alzheimer’s brains transmit tau pathology in nontransgenic mice. J. Exp. Med. 213, 2635–2654 (2016).

    Article  CAS  Google Scholar 

  5. Rauch, J. N. et al. Tau internalization is regulated by 6-O sulfation on heparan sulfate proteoglycans (HSPGs). Sci. Rep. 8, 6382 (2018).

    Article  ADS  Google Scholar 

  6. Holmes, B. B. et al. Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc. Natl Acad. Sci. USA 110, E3138–E3147 (2013).

    Article  CAS  Google Scholar 

  7. Kanekiyo, T. et al. Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-β uptake. J. Neurosci. 31, 1644–1651 (2011).

    Article  CAS  Google Scholar 

  8. Evans, L. D. et al. Extracellular monomeric and aggregated tau efficiently enter human neurons through overlapping but distinct pathways. Cell Rep. 22, 3612–3624 (2018).

    Article  CAS  Google Scholar 

  9. De Nardis, C. et al. Recombinant expression of the full-length ectodomain of LDL receptor-related protein 1 (LRP1) unravels pH-dependent conformational changes and the stoichiometry of binding with receptor-associated protein (RAP). J. Biol. Chem. 292, 912–924 (2017).

    Article  Google Scholar 

  10. Dolmer, K., Campos, A. & Gettins, P. G. Quantitative dissection of the binding contributions of ligand lysines of the receptor-associated protein (RAP) to the low density lipoprotein receptor-related protein (LRP1). J. Biol. Chem. 288, 24081–24090 (2013).

    Article  CAS  Google Scholar 

  11. Nikolic, J. et al. Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein. Nat. Commun. 9, 1029 (2018).

    Article  ADS  Google Scholar 

  12. Fisher, C., Beglova, N. & Blacklow, S. C. Structure of an LDLR-RAP complex reveals a general mode for ligand recognition by lipoprotein receptors. Mol. Cell 22, 277–283 (2006).

    Article  CAS  Google Scholar 

  13. Lillis, A. P., Van Duyn, L. B., Murphy-Ullrich, J. E. & Strickland, D. K. LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol. Rev. 88, 887–918 (2008).

    Article  CAS  Google Scholar 

  14. Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).

    Article  ADS  CAS  Google Scholar 

  15. Falcon, B. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019).

    Article  ADS  CAS  Google Scholar 

  16. Xing, P. et al. Roles of low-density lipoprotein receptor-related protein 1 in tumors. Chin. J. Cancer 35, 6 (2016).

    Article  Google Scholar 

  17. Andersen, O. M. & Willnow, T. E. Lipoprotein receptors in Alzheimer’s disease. Trends Neurosci. 29, 687–694 (2006).

    Article  CAS  Google Scholar 

  18. Nakajima, C. et al. Low density lipoprotein receptor-related protein 1 (LRP1) modulates N-methyl-D-aspartate (NMDA) receptor-dependent intracellular signaling and NMDA-induced regulation of postsynaptic protein complexes. J. Biol. Chem. 288, 21909–21923 (2013).

    Article  CAS  Google Scholar 

  19. Wegmann, S. et al. Experimental evidence for the age dependence of tau protein spread in the brain. Sci. Adv. 5, eaaw6404 (2019).

    Article  ADS  Google Scholar 

  20. Szymczak, A. L. et al. Correction of multi-gene deficiency in vivo using a single ‘self-cleaving’ 2A peptide-based retroviral vector. Nat. Biotechnol. 22, 589–594 (2004).

    Article  CAS  Google Scholar 

  21. Auderset, L., Cullen, C. L. & Young, K. M. Low density lipoprotein-receptor related protein 1 is differentially expressed by neuronal and glial populations in the developing and mature mouse central nervous system. PLoS ONE 11, e0155878 (2016).

    Article  Google Scholar 

  22. Shinohara, M., Tachibana, M., Kanekiyo, T. & Bu, G. Role of LRP1 in the pathogenesis of Alzheimer’s disease: evidence from clinical and preclinical studies. J. Lipid Res. 58, 1267–1281 (2017).

    Article  CAS  Google Scholar 

  23. Tachibana, M. et al. APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1. J. Clin. Invest. 129, 1272–1277 (2019).

    Article  Google Scholar 

  24. Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).

    Article  ADS  Google Scholar 

  25. Mahley, R. W. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol. 36, 1305–1315 (2016).

    Article  CAS  Google Scholar 

  26. Christianson, H. C. & Belting, M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol. 35, 51–55 (2014).

    Article  CAS  Google Scholar 

  27. Horlbeck, M. A. et al. Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation. eLife 5, e19760 (2016).

    Article  Google Scholar 

  28. Obermoeller-McCormick, L. M. et al. Dissection of receptor folding and ligand-binding property with functional minireceptors of LDL receptor-related protein. J. Cell Sci. 114, 899–908 (2001).

    CAS  PubMed  Google Scholar 

  29. Despres, C. et al. Identification of the tau phosphorylation pattern that drives its aggregation. Proc. Natl Acad. Sci. USA 114, 9080–9085 (2017).

    Article  CAS  Google Scholar 

  30. Usenovic, M. et al. Internalized tau oligomers cause neurodegeneration by inducing accumulation of pathogenic tau in human neurons derived from induced pluripotent stem cells. J. Neurosci. 35, 14234–14250 (2015).

    Article  CAS  Google Scholar 

  31. Tian, R. et al. CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron 104, 239–255 (2019).

    Article  CAS  Google Scholar 

  32. Challis, R. C. et al. Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat. Protoc. 14, 379–414 (2019).

    Article  CAS  Google Scholar 

  33. Chan, K. Y. et al. Engineered AAVs for efficient noninvasive gene delivery to the central and peripheral nervous systems. Nat. Neurosci. 20, 1172–1179 (2017).

    Article  CAS  Google Scholar 

  34. Luna, G. et al. The effects of transient retinal detachment on cavity size and glial and neural remodeling in a mouse model of X-linked retinoschisis. Invest. Ophthalmol. Vis. Sci. 50, 3977–3984 (2009).

    Article  Google Scholar 

Download references

Acknowledgements

This study was funded by the National Institutes of Health (NIH), K99 AG064116 (J.N.R.), DP2 GM119139 (M.K.), R01 AG062359 (M.K.), R56 AG057528 (M.K.), U54 NS 100717 (M.K., K.S.K.), Tau Consortium (M.K., K.S.K.), German Center for Neurodegenerative Diseases (S.W.), Ben Barres Early Career Acceleration Award from the Chan Zuckerberg Initiative (M.K.), Tri-counties Blood Bank (J.N.R.), Dr Miriam and Sheldon G. Adelson Medical Research Foundation (K.S.K.), Larry L. Hillblom Foundation (K.S.K.) and Edward N. & Della L. Thome Memorial Foundation (K.S.K.). We thank the Laboratory for Stem Cell Biology and Engineering at UCSB for use of their flow cytometer, the Neuroscience Research Institute Microscopy Facility for use of their microscopes, J. Dong for help in the early stages of this project and P. Davies for providing the MC-1 antibody.

Author information

Authors and Affiliations

  1. Neuroscience Research Institute, Department of Molecular, Cellular, and Developmental Biology, University of California, Santa Barbara, CA, USA

    Jennifer N. Rauch, Gabriel Luna, Elmer Guzman, Morgane Audouard, Youssef E. Sibih, Carolina Leshuk, Israel Hernandez & Kenneth S. Kosik

  2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA

    Collin Challis & Viviana Gradinaru

  3. German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany

    Susanne Wegmann

  4. Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Bradley T. Hyman

  5. Institute for Neurodegenerative Diseases, Department of Biochemistry and Biophysics, The California Institute for Quantitative Biomedical Research, Quantitative Biosciences Institute, University of California, San Francisco, CA, USA

    Martin Kampmann

  6. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Martin Kampmann

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  1. Jennifer N. Rauch
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Contributions

J.N.R. and K.S.K. conceived the study. J.N.R. and K.S.K. designed the study. J.N.R. performed most of the experiments and analysed the data, assisted by G.L., E.G., M.A., C.C., Y.E.S., C.L. and I.H. C.C., V.G., S.W. and B.T.H. provided AAVs used in the study. M.K. provided CRISPRi cell lines. J.N.R. and K.S.K. wrote the manuscript, and all authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Kenneth S. Kosik.

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Competing interests

K.S.K. is on the Board of Directors of the Rainwater Charitable Trust.

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Peer review information Nature thanks Katrin Deinhardt, Joachim Herz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data figures and tables

Extended Data Fig. 1 Tau uptake is regulated by LRP1.

a, Gating strategy for tau uptake assay. First, cells were gated on forward scatter/side scatter (FSC/SSC; mean FSC-A, around 8,000,000; mean SSC-A, around 800,000). Cells were then gated on forward scatter height (FSC-H) versus width to discriminate doublets. Dead cells were removed from the analysis using propidium iodide as a stain, and positive cells were determined by gating on a negative (no tau added) population. b, Internalization controls for tau uptake assay (n = 6). c, Quantitative PCR analysis of various genes with sgRNA in H4i cells. The first column represents the NT sgRNA control for each target (n = 3). d, Uptake of phosphorylated (p2N4R) or mutated (2N4RP301L) full-length tau in H4i cells (n = 8). e, Western blot analysis of LRP1 in wild-type, NT sgRNA or LRP1 sgRNA H4i cells. All results in b–e were obtained in three independent experiments and normalized to wild-type uptake (100%). Data are expressed as mean ± s.d. with individual data points shown. One-way ANOVA with Tukey’s method, two-sided was performed to determine significance; ****P < 0.0001.

Source Data

Extended Data Fig. 2 LRP1 ligands influence tau uptake.

a, Uptake of 2N4R tau with competition from RAP or lysine-capped RAP. b, Uptake of 2N4R tau with competition from RAP or mtRAP. c, Corrected integrated density of surface HA staining for different ectodomain cell lines (n = 60). d, Co-immunoprecipitation of HA–mLRP4 with myc–2N4R (n = 3). e, Uptake of various ligands at indicated concentrations (1 h). f, Western blot analysis of conditioned medium (CM) from HEK293T cells, mock-treated or overexpressing ApoE (n = 3). g, Uptake of full-length tau and transferrin in conditioned medium from f (n = 9). All experiments in a, b, e were performed in biological duplicate over three independent experiments (n = 6) with representative experiments shown. Data are expressed as mean ± s.d. with individual data points shown. One-way ANOVA with Tukey’s method, two-sided was performed to determine significance; ****P < 0.0001.

Source Data

Extended Data Fig. 3 LRP1 expression influences tau spread.

a, Quantitative PCR analysis of LRP1 expression in iPSNs (n = 3; P < 0.0001). b, Quantitative PCR analysis of LRP1 expression from mouse cortex transduced with human synapsin (hSyn) scramble shRNA or LRP1 shRNA (n = 3; P = 0.0412). c, Quantification of tau spread in mice broken down by sex (males n = 4, females n = 3; two-way ANOVA, sex = NS, P = 0.5335). d, Immunofluorescence of mouse primary culture transduced with AAVmRuby-hSyn-shLRP1 (green, Tau; red, mRuby; blue, Hoechst; scale bar, 20 μm, n = 3). d, Immunohistochemistry of hTau+ astrocytes in mice injected with PBS (green, Sox2; red, hTau; blue, Hoechst; scale bar, 20 μm, n = 3). e, Immunohistochemistry of mice injected with scramble shRNA and LRP1 shRNA (green, LRP1; blue; Hoechst, scale bars, 20 μm; n = 3). Unpaired t-test, two-tailed was performed to determine statistical significance for quantitative PCR in a, b; *P ≤ 0.05, ****P < 0.0001.

Source Data

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Rauch, J.N., Luna, G., Guzman, E. et al. LRP1 is a master regulator of tau uptake and spread. Nature 580, 381–385 (2020). https://doi.org/10.1038/s41586-020-2156-5

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