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Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation

Nature Structural & Molecular Biology volume 29, pages 292–305 (2022)Cite this article

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Abstract

The noradrenergic locus ceruleus (LC) is the first site of detectable tau pathology in Alzheimer’s disease (AD), but the mechanisms underlying the selective vulnerability of the LC in AD have not been completely identified. In the present study, we show that DOPEGAL, a monoamine oxidase A (MAO-A) metabolite of norepinephrine (NE), reacts directly with the primary amine on the Lys353 residue of tau to stimulate its aggregation and facilitate its propagation. Inhibition of MAO-A or mutation of the Lys353 residue to arginine (Lys353Arg) decreases tau Lys353–DOPEGAL levels and diminishes tau pathology spreading. Wild-type tau preformed fibrils (PFFs) trigger Lys353–DOPEGAL formation, tau pathology propagation and cognitive impairment in MAPT transgenic mice, all of which are attenuated with PFFs made from the Lys353Arg mutant. Thus, the selective vulnerability of LC neurons in AD may be explained, in part, by NE oxidation via MAO-A into DOPEGAL, which covalently modifies tau and accelerates its aggregation, toxicity and propagation.

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Fig. 1: DOPEGAL modifies tau Lys353 residue and mediates tau aggregation.
Fig. 2: DOPEGAL modification of tau promotes its aggregation and seeding.
Fig. 3: Tau modification by DOPEGAL induces AEP activation, tau pathology and cell death in neurons.
Fig. 4: DOPEGAL is upregulated and modifies tau at Lys353 in the progression of AD.
Fig. 5: Inhibition of MAO-A reduces DOPEGAL-tau modification and tau pathology in tau P301S mice.
Fig. 6: Lys353Arg mutation is unable to initiate or propagate tau pathology and memory dysfunctions in tau−/− mice.
Fig. 7: Mutation of Lys353Arg is resistant to tau fibrillization and propagation in MAPT mouse brain.

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Data availability

The authors declare that all data supporting the findings of the present study are available within the article and Source data files. Source data are provided with this paper.

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Acknowledgements

We thank the Emory Goizueta Alzheimer’s Disease Research Center for postmortem human AD and healthy control samples. This work was supported by the National Institutes for Health (NIH; grant no. RF1 AG061175 to S.S.K. and D.W.), the National Natural Science Foundation of China (grant no. 81822016 to Z.Z.) and the National Key Basic Research Program of China Grant (grant no, 2019YFE0115900 to Z.Z.). Additional support was provided by the Emory Neuroscience National Institute of Neurological Disorders Core Facilities (grant no. P30NS055077). Further support was provided by the Georgia Clinical & Translational Science Alliance of the NIH under award no. UL1TR002378. The present study was supported in part by the Rodent Behavioral Core, Viral Vector Core and HPLC Bioanalytical Core, which are subsidized by the Emory University School of Medicine and are part of the Emory Integrated Core Facilities.

Author information

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA

    Seong Su Kang, Xia Liu & Keqiang Ye

  2. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China

    Lanxia Meng, Xingyu Zhang & Zhentao Zhang

  3. Departments of Structural Biology and Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Zhiping Wu, Ariana Mancieri, Boer Xie & Junmin Peng

  4. Center for Proteomics and Metabolomics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Zhiping Wu, Ariana Mancieri, Boer Xie & Junmin Peng

  5. Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, USA

    David Weinshenker

  6. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, China

    Keqiang Ye

  7. The Brain Cognition and Brain Disease Institute, Shenzhen Institute of Advanced Technology, Shenzhen, China

    Keqiang Ye

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Contributions

K.Y. and Z.Z. conceived the project, designed the experiments and analyzed the data. K.Y. wrote the manuscript. S.S.K. designed and performed most of the experiments and analyzed the data. X.L. prepared primary neurons and assisted with animal experiments. L.M. and X.Z. performed tau fibrillation in vitro experiments. Z.W., A.M. and J.P. performed LC–MS/MS experiments and assisted data analysis. D.W. helped design the experiments and edited the manuscript.

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Correspondence to Zhentao Zhang or Keqiang Ye.

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Extended data

Extended Data Fig. 1 Biophysical characterization of recombinant Tau and Tau K353R mutant fibrils.

A. X-ray diffraction assay demonstrating characters of fibrils generated from Tau, Tau K353R, Tau N368, and Tau N368 K353R protein. B. Quantification table showed that DOPEGAL increased the counts of β-sheet at around 4.8 Å for Tau and Tau N368, but not Tau K353R and Tau N368 K353R. C. LC-MS/MS spectrum confirming DOPEGAL-modified Tau residue at K353 by the application of GluC digestion for the protein samples. D. Recombinant wild-type and K353R Tau were induced to aggregate into PFFs in the presence or absence of DOPEGAL. The PFFs were digested with Protease K (2 μg/ml). All data are representatives of three independent experiments with similar results. E. Recombinant Tau and Tau N368 were incubated with DOPEGAL (500 μM) for 0, 5, 30, and 60 minutes. Western blot and densitometric quantification of TauK353-DOPEGAL band showed that Tau N368 is more prone to be modified by DOPEGAL than full-length Tau. All data are shown as mean ± SEM. n = 3 per group. Paired Student t-test.

Source data

Extended Data Fig. 2 DOPEGAL promotes tau aggregation, attenuated by Tau K353R mutation.

A. Representative images showing the co-localization of aggregated tau with ubiquitin in tau PFF-treated HEK293 cells stably transfected with GFP-Tau RD in the presence or absence of DOPEGAL. Scale bar is 20 μm. B. HEK293 cells were transfected with wild-type or K353R mutant Tau RD, treated with DOPEGAL, and then transduced with tau PFFs. The green dots show tau inclusions. Scale bar is 20 μm. C. Quantification of the percentage of cells with tau inclusions. Data are shown as mean ± SEM. n = 10 per group. One-way ANOVA. D. The cells were sequentially extracted with 1% Triton X-100 lysis buffer followed by 2% SDS. Cell lysates from Triton X-100 soluble and SDS-soluble fractions were immunoblotted with GFP antibody. E. Quantification of the relative concentration of tau in the Triton X-100 soluble and SDS-soluble fractions. Data are shown as mean ± SEM. n = 4 per group. One-way ANOVA. F. The HEK293 cells stably transfected with GFP-Tau RD were exposed to DOPEGAL. The phosphorylation of tau at S202 was analyzed by immunofluorescence (red) and western blot. All data and images are representatives of three independent experiments with similar results.

Source data

Extended Data Fig. 3 DOPEGAL modification at Tau K353 is dependent on NE.

Tau P301S/DBH + /- and Tau P301S/DBH-/- mice of 3 months and 9 months old were examined for DOPEGAL modification and phosphorylation of Tau in the LC by immunofluorescence staining. A. Representative images of DBH (green), Tau K353-DOPEGAL (red), and DAPI (blue), AT8 (green), Tau K353-DOPEGAL (red), and DAPI (blue) staining in LC sections of Tau P301S/DBH + /- and Tau P301S/DBH-/- mice. Scale bar = 100 μm. B. Quantification of Tau K353-DOPEGAL/AT8 + cells. Data are shown as mean ± SEM. n = 6 per group. Two-way ANOVA with Sidak’s multiple comparison.

Source data

Extended Data Fig. 4 DOPEGAL modification of Tau is regulated by AEP and MAO-A.

DOPEGAL (0.25 μg) was injected into the LC regions of MAPT and MAPT/AEP-/- mice. DOPEGAL modification and cleavage of Tau in the LC were examined by immunofluorescence staining. A. Representative images of DBH (green), TauK353-DOPEGAL (red), and DAPI (blue); Tau N368 (green), TauK353-DOPEGAL (red), and DAPI (blue) staining in LC sections of DOPEGAL-injected MAPT and MAPT/AEP-/- mice. Scale bar is 100 μm. B,C. Quantification of TauK353-DOPEGAL + (B) and Tau N368 + cells (C). Data are shown as mean ± SEM. n = 6 per group. Two-way ANOVA with Sidak’s multiple comparison. D. AAV-control or AAV-MAO-A was injected into the LC regions of MAPT mice. Neuronal cell death (TUNEL) and DOPEGAL modification (Tau K353-DOPEGAL), cleavage (Tau N368), phosphorylation (AT8), and aggregation (T22) of Tau in the LC were examined by immunofluorescence staining. Scale bar is 100 μm. E. Co-stained positive cells were quantified in the LC of AAV-injected MAPT mice. Data are shown as mean ± SEM. n = 6 per group. Student t-test.

Source data

Extended Data Fig. 5 Inhibition of MAO-A reduces DOPEGAL-Tau modification and Tau pathology in P301S mice.

MAO-A inhibitor clorgyline was administered in 3-month-old tau P301S mice for 3 months (3 mg/kg/day). A,B. Representative images of immunofluorescent staining for Tau K353-DOPEGAL (green), Tau N368 (red), and DAPI (blue) (A) and Tau K353-DOPEGAL (green); AT8 (red); DAPI (blue) (B). Scale bars are 100 μm (left) and 20 μm (right). C. Quantification of Tau K353-DOPEGAL/TauN368+ and Tau K353-DOPEGAL/AT8 + cells in the LC sections of vehicle- or clorgyline-treated Tau P301S mice. Data are shown as mean ± SEM. n = 6 mice per group. Student t-test.

Source data

Extended Data Fig. 6 Tau K353R mutation blocks tau pathology spreading from the LC to the forebrain in Tau -/- mice.

AAV-control, AAV-Tau, and AAV-Tau K353R were injected into the LC of 3-month-old Tau -/- mice. The mice were assessed for Tau cleavage and phosphorylation 3 months after injection. A,B. Representative images of immunofluorescent staining for Tau K353-DOPEGAL (green); Tau N368 (red); DAPI (blue) (A) and Tau K353-DOPEGAL (green); AT8 (red); DAPI (blue) (B). Scale bars are 100 μm (left) and 20 μm (right). C. Quantification of Tau N368 + and AT8 + cells in the LC sections. Data are shown as mean ± SEM. n = 6 mice per group. Two-way ANOVA with Sidak’s multiple comparison. D. Quantitative PCR demonstrating the expression of human Tau in LC, EC, and HC at 3 months after viral injection. Data are shown as mean ± SEM. n = 4. Two-way ANOVA with Sidak’s multiple comparison. E. Representative images of immunohistochemistry staining for Tau K353-DOPEGAL on the LC, EC, and HC sections at 1 month after AAV-Tau injection into LC of Tau-/- mice. Scale bar is 200 μm. F. K353-DOPEGAL/NeuN or K353-DOPEGAL/DBH immunofluorescent co-staining on the EC or HC of Tau -/- mice. Tau K353-DOPEGAL (green)/NeuN or DBH (red); Tau K353-DOPEGAL (red)/ DBH (green)/DAPI (blue). Scale bar is100 μm. All images of E & F are representatives of three independent experiments with similar results.

Source data

Extended Data Fig. 7 Tau PFFs fail to induce tau pathology in Tau-/- mice.

Pre-formed fibrils (PFFs) of Tau or Tau K353R were injected into the LC of 3-month-old Tau -/- mice. The mice were assessed for DOPEGAL modification and phosphorylation of Tau 3 months later. A, B. Representative images of immunofluorescent staining for Tau K353-DOPEGAL (red); DBH (green); DAPI (blue) (A) and Tau K353-DOPEGAL (green); AT8 (red); DAPI (blue) (B). Scale bars are 100 μm (left) and 20 μm (right). C. Quantification of DBH + cells in the LC sections of PBS, Tau, or Tau K353R PFFs-injected Tau-/- mice. Data are shown as mean ± SEM. n = 8 per group. One-way ANOVA. D. Quantification of Tau K353-DOPEGAL + and AT8 + cells in the LC sections of PFFs-injected Tau -/- mice. Data are shown as mean ± SEM. n = 6 per group. Two-way ANOVA with Sidak’s multiple comparison.

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Kang, S.S., Meng, L., Zhang, X. et al. Tau modification by the norepinephrine metabolite DOPEGAL stimulates its pathology and propagation. Nat Struct Mol Biol 29, 292–305 (2022). https://doi.org/10.1038/s41594-022-00745-3

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