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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Goedert, M., Eisenberg, D. S. & Crowther, R. A. Propagation of tau aggregates and neurodegeneration. Annu. Rev. Neurosci. 40, 189–210 (2017).
Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).
de Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).
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).
Rauch, J. N. et al. Tau internalization is regulated by 6-O sulfation on heparan sulfate proteoglycans (HSPGs). Sci. Rep. 8, 6382 (2018).
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).
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).
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).
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).
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).
Nikolic, J. et al. Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein. Nat. Commun. 9, 1029 (2018).
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).
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).
Fitzpatrick, A. W. P. et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547, 185–190 (2017).
Falcon, B. et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature 568, 420–423 (2019).
Xing, P. et al. Roles of low-density lipoprotein receptor-related protein 1 in tumors. Chin. J. Cancer 35, 6 (2016).
Andersen, O. M. & Willnow, T. E. Lipoprotein receptors in Alzheimer’s disease. Trends Neurosci. 29, 687–694 (2006).
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).
Wegmann, S. et al. Experimental evidence for the age dependence of tau protein spread in the brain. Sci. Adv. 5, eaaw6404 (2019).
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).
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).
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).
Tachibana, M. et al. APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1. J. Clin. Invest. 129, 1272–1277 (2019).
Shi, Y. et al. ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549, 523–527 (2017).
Mahley, R. W. Central nervous system lipoproteins: ApoE and regulation of cholesterol metabolism. Arterioscler. Thromb. Vasc. Biol. 36, 1305–1315 (2016).
Christianson, H. C. & Belting, M. Heparan sulfate proteoglycan as a cell-surface endocytosis receptor. Matrix Biol. 35, 51–55 (2014).
Horlbeck, M. A. et al. Compact and highly active next-generation libraries for CRISPR-mediated gene repression and activation. eLife 5, e19760 (2016).
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).
Despres, C. et al. Identification of the tau phosphorylation pattern that drives its aggregation. Proc. Natl Acad. Sci. USA 114, 9080–9085 (2017).
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).
Tian, R. et al. CRISPR interference-based platform for multimodal genetic screens in human iPSC-derived neurons. Neuron 104, 239–255 (2019).
Challis, R. C. et al. Systemic AAV vectors for widespread and targeted gene delivery in rodents. Nat. Protoc. 14, 379–414 (2019).
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).
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).
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.
K.S.K. is on the Board of Directors of the Rainwater Charitable Trust.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
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
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
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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