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Cited by 75Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

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Mangleburg, Carl Grant, Wu, Timothy, Yalamanchili, Hari K., Guo, Caiwei, Hsieh, Yi-Chen, Duong, Duc M., Dammer, Eric B., De Jager, Philip L. +3 more·2020·Molecular Neurodegeneration
DOI 10.1186/s13024-020-00405-4PMC PMC7526226

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Abstract

Background: Tau neurofibrillary tangle pathology characterizes Alzheimer’s disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau- versus age-dependent changes. Methods: Paired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau WT ) or a mutant form causing frontotemporal dementia (Tau R406W ). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. Results: Tau WT induced 1514 and 213 differentially expressed transcripts and proteins, respectively. Tau R406W had a substantially greater impact, causing changes in 5494 transcripts and 697 proteins. There was a ~ 70% overlap between age- and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. Conclusions: Our results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome.

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  • Discordance or decoupling in mRNA and protein expression of the same genes has been reported in human aging and neurodegenerative disorders such as tauopathy and AD.

    “The discordance or decoupling in mRNA and protein expression of the same genes has been reported in studies with human aging [67] and neurodegenerative disorders such as tauopathy [68] and AD [69]”

    From Sex specific molecular networks and key drivers of Alzheimer’s disease (2023) · cites this paper as [68]

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  1. [1]Iqbal K Liu F Gong C-X Tau and neurodegenerative disease: the story so far Nat Rev Neurol 2016 12 1 15 27 10.1038/nrneurol.2015.225 26635213 · DOI · Paper page
  2. [2]Spillantini MG Goedert M Tau pathology and neurodegeneration Lancet Neurol 2013 12 6 609 622 10.1016/S1474-4422(13)70090-5 23684085 · DOI · Paper page
  3. [3]Hutton M Lendon CL Rizzu P Baker M Froelich S Houlden H Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17 Nature. 1998 393 6686 702 705 10.1038/31508 9641683 · DOI · Paper page
  4. [4]Poorkaj P Bird TD Wijsman E Nemens E Garruto RM Anderson L Tau is a candidate gene for chromosome 17 frontotemporal dementia Ann Neurol 1998 43 6 815 825 10.1002/ana.410430617 9629852 · DOI · Paper page
  5. [5]Spillantini MG Murrell JR Goedert M Farlow MR Klug A Ghetti B Mutation in the tau gene in familial multiple system tauopathy with presenile dementia Proc Natl Acad Sci U S A 1998 95 13 7737 7741 10.1073/pnas.95.13.7737 9636220 PMC22742 · DOI · Paper page
  6. [6]Gistelinck M Lambert J-C Callaerts P Dermaut B Dourlen P Drosophila models of tauopathies: what have we learned? Int J Alzheimers Dis 2012 2012 970980 22701808 PMC3373119
  7. [7]Götz J Bodea L-G Goedert M Rodent models for Alzheimer disease Nat Rev Neurosci 2018 19 10 583 598 10.1038/s41583-018-0054-8 30194347 · DOI
  8. [8]Wang Y Mandelkow E Tau in physiology and pathology Nat Rev Neurosci 2016 17 1 22 35 10.1038/nrn.2015.1 26631930 · DOI · Paper page
  9. [11]Mostafavi S Gaiteri C Sullivan SE White CC Tasaki S Xu J A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease Nat Neurosci 2018 21 6 811 819 10.1038/s41593-018-0154-9 29802388 PMC6599633 · DOI · Paper page
  10. [12]Reynolds RH Hardy J Ryten M Gagliano Taliun SA Informing disease modelling with brain-relevant functional genomic annotations Brain. 2019 142 12 3694 3712 10.1093/brain/awz295 31603214 PMC6885670 · DOI
  11. [13]Jack CR Knopman DS Jagust WJ Petersen RC Weiner MW Aisen PS Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers Lancet Neurol 2013 12 2 207 216 10.1016/S1474-4422(12)70291-0 23332364 PMC3622225 · DOI · Paper page
  12. [15]Kapasi A DeCarli C Schneider JA Impact of multiple pathologies on the threshold for clinically overt dementia Acta Neuropathol 2017 134 2 171 186 10.1007/s00401-017-1717-7 28488154 PMC5663642 · DOI · Paper page
  13. [16]de Sousa Abreu R Penalva LO Marcotte EM Vogel C Global signatures of protein and mRNA expression levels Mol BioSyst 2009 5 12 1512 1526 20023718 PMC4089977
  14. [17]Seyfried NT Dammer EB Swarup V Nandakumar D Duong DM Yin L A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer’s Disease Cell Syst 2017 4 1 60 72 10.1016/j.cels.2016.11.006 27989508 PMC5269514 · DOI · Paper page
  15. [18]Johnson ECB Dammer EB Duong DM Ping L Zhou M Yin L Large-scale proteomic analysis of Alzheimer’s disease brain and cerebrospinal fluid reveals early changes in energy metabolism associated with microglia and astrocyte activation Nat Med 2020 26 5 769 780 10.1038/s41591-020-0815-6 32284590 PMC7405761 · DOI · Paper page
  16. [19]Gjoneska E Pfenning AR Mathys H Quon G Kundaje A Tsai L-H Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease Nature. 2015 518 7539 365 369 10.1038/nature14252 25693568 PMC4530583 · DOI · Paper page
  17. [20]Wang H Li Y Ryder JW Hole JT Ebert PJ Airey DC Genome-wide RNAseq study of the molecular mechanisms underlying microglia activation in response to pathological tau perturbation in the rTg4510 tau transgenic animal model Mol Neurodegener 2018 13 1 65 10.1186/s13024-018-0296-y 30558641 PMC6296031 · DOI · Paper page
  18. [21]Kim J Selvaraji S Kang SW Lee WT Chen CL-H Choi H Cerebral transcriptome analysis reveals age-dependent progression of neuroinflammation in P301S mutant tau transgenic male mice Brain Behav Immun 2019 80 344 357 10.1016/j.bbi.2019.04.011 30980950 · DOI
  19. [22]Wittmann CW Wszolek MF Shulman JM Salvaterra PM Lewis J Hutton M Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles Science. 2001 293 5530 711 714 10.1126/science.1062382 11408621 · DOI · Paper page
  20. [23]Shulman JM Feany MB Genetic modifiers of tauopathy in Drosophila Genetics. 2003 165 3 1233 1242 14668378 PMC1462852
  21. [26]Shulman JM Chipendo P Chibnik LB Aubin C Tran D Keenan BT Functional screening of Alzheimer pathology genome-wide association signals in Drosophila Am J Hum Genet 2011 88 2 232 238 10.1016/j.ajhg.2011.01.006 21295279 PMC3035702 · DOI
  22. [27]Chapuis J Hansmannel F Gistelinck M Mounier A Van Cauwenberghe C Kolen KV Increased expression of BIN1 mediates Alzheimer genetic risk by modulating tau pathology Mol Psychiatry 2013 18 11 1225 1234 10.1038/mp.2013.1 23399914 PMC3807661 · DOI · Paper page
  23. [29]Scherzer CR Jensen RV Gullans SR Feany MB Gene expression changes presage neurodegeneration in a Drosophila model of Parkinson’s disease Hum Mol Genet 2003 12 19 2457 2466 10.1093/hmg/ddg265 12915459 · DOI
  24. [32]Dobin A Davis CA Schlesinger F Drenkow J Zaleski C Jha S STAR: ultrafast universal RNA-seq aligner Bioinformatics. 2013 29 1 15 21 10.1093/bioinformatics/bts635 23104886 PMC3530905 · DOI · Paper page
  25. [33]Becht E McInnes L Healy J Dutertre C-A Kwok IWH Ng LG Dimensionality reduction for visualizing single-cell data using UMAP Nat Biotechnol 2019 37 1 38 44 10.1038/nbt.4314 30531897 · DOI · Paper page
  26. [34]Lim MY Paulo JA Gygi SP Evaluating false transfer rates from the match-between-runs algorithm with a two-proteome model J Proteome Res 2019 18 11 4020 4026 10.1021/acs.jproteome.9b00492 31547658 PMC7346880 · DOI
  27. [35]Tyanova S Temu T Sinitcyn P Carlson A Hein MY Geiger T The Perseus computational platform for comprehensive analysis of (prote)omics data Nat Methods 2016 13 9 731 740 10.1038/nmeth.3901 27348712 · DOI
  28. [36]Love MI Huber W Anders S Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 Genome Biol 2014 15 12 550 10.1186/s13059-014-0550-8 25516281 PMC4302049 · DOI · Paper page
  29. [37]Millstein J Volfson D Computationally efficient permutation-based confidence interval estimation for tail-area FDR Front Genet 2013 4 179 24062767 PMC3775454
  30. [38]Therneau TM Grambsch PM Modeling survival data: extending the cox model 2000 New York Springer-Verlag
  31. [39]Liao Y Wang J Jaehnig EJ Shi Z Zhang B WebGestalt 2019: gene set analysis toolkit with revamped UIs and APIs Nucleic Acids Res 2019 47 W1 W199 W205 10.1093/nar/gkz401 31114916 PMC6602449 · DOI · Paper page
  32. [40]Gaujoux R Seoighe C A flexible R package for nonnegative matrix factorization BMC Bioinformatics 2010 11 1 367 10.1186/1471-2105-11-367 20598126 PMC2912887 · DOI
  33. [41]Langfelder P Horvath S WGCNA: an R package for weighted correlation network analysis BMC Bioinformatics 2008 9 1 559 10.1186/1471-2105-9-559 19114008 PMC2631488 · DOI · Paper page
  34. [42]Hu Y Flockhart I Vinayagam A Bergwitz C Berger B Perrimon N An integrative approach to ortholog prediction for disease-focused and other functional studies BMC Bioinformatics 2011 12 357 10.1186/1471-2105-12-357 21880147 PMC3179972 · DOI
  35. [43]Hu Y Sopko R Foos M Kelley C Flockhart I Ammeux N FlyPrimerBank: an online database for Drosophila melanogaster gene expression analysis and knockdown evaluation of RNAi reagents. G3: genes Genomes Genetics 2013 3 9 1607 1616 PMC3755921 23893746
  36. [44]Yoshiga T Georgieva T Dunkov BC Harizanova N Ralchev K Law JH Drosophila melanogaster transferrin Eur J Biochem 1999 260 2 414 420 10.1046/j.1432-1327.1999.00173.x 10095776 · DOI
  37. [45]Littleton JT Stern M Schulze K Perin M Bellen HJ Mutational analysis of Drosophila synaptotagmin demonstrates its essential role in Ca2+−activated neurotransmitter release Cell. 1993 74 6 1125 1134 10.1016/0092-8674(93)90733-7 8104705 · DOI
  38. [46]Merlo P Frost B Peng S Yang YJ Park PJ Feany M p53 prevents neurodegeneration by regulating synaptic genes PNAS. 2014 111 50 18055 18060 10.1073/pnas.1419083111 25453105 PMC4273405 · DOI
  39. [47]Broadie K Prokop A Bellen HJ O’Kane CJ Schulze KL Sweeney ST Syntaxin and synaptobrevin function downstream of vesicle docking in drosophila Neuron. 1995 15 3 663 673 10.1016/0896-6273(95)90154-X 7546745 · DOI
  40. [48]Ivan V de Voer G Xanthakis D Spoorendonk KM Kondylis V Rabouille C Drosophila Sec16 mediates the biogenesis of tER sites upstream of Sar1 through an arginine-rich motif MBoC. 2008 19 10 4352 4365 10.1091/mbc.e08-03-0246 18614796 PMC2555954 · DOI
  41. [49]Valakh V Walker LJ Skeath JB DiAntonio A Loss of the Spectraplakin short stop activates the DLK injury response pathway in Drosophila J Neurosci 2013 33 45 17863 17873 10.1523/JNEUROSCI.2196-13.2013 24198375 PMC3818558 · DOI
  42. [50]Kounatidis I Chtarbanova S Cao Y Hayne M Jayanth D Ganetzky B NF-κB immunity in the brain determines Fly lifespan in healthy aging and age-related Neurodegeneration Cell Rep 2017 19 4 836 848 10.1016/j.celrep.2017.04.007 28445733 PMC5413584 · DOI
  43. [54]Al-Ramahi I Lu B Paola SD Pang K de Haro M Peluso I High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration Cell Syst 2018 7 1 28 40 10.1016/j.cels.2018.05.010 29936182 PMC6082401 · DOI
  44. [56]Lee TV Ding T Chen Z Rajendran V Scherr H Lackey M The E1 ubiquitin-activating enzyme Uba1 in Drosophila controls apoptosis autonomously and tissue growth non-autonomously Development. 2008 135 1 43 52 10.1242/dev.011288 18045837 PMC2277323 · DOI
  45. [57]Watts RJ Hoopfer ED Luo L Axon pruning during Drosophila metamorphosis: evidence for local degeneration and requirement of the ubiquitin-proteasome system Neuron. 2003 38 6 871 885 10.1016/S0896-6273(03)00295-2 12818174 · DOI
  46. [59]Aviner R Shenoy A Elroy-Stein O Geiger T Uncovering hidden layers of cell cycle regulation through integrative multi-omic analysis PLoS Genet 2015 11 10 e1005554 10.1371/journal.pgen.1005554 26439921 PMC4595013 · DOI
  47. [60]Hartl D Irmler M Römer I Mader MT Mao L Zabel C Transcriptome and proteome analysis of early embryonic mouse brain development Proteomics. 2008 8 6 1257 1265 10.1002/pmic.200700724 18283662 · DOI
  48. [61]Lahtvee P-J Sánchez BJ Smialowska A Kasvandik S Elsemman IE Gatto F Absolute Quantification of Protein and mRNA Abundances Demonstrate Variability in Gene-Specific Translation Efficiency in Yeast Cell Syst 2017 4 5 495 504 10.1016/j.cels.2017.03.003 28365149 · DOI · Paper page
  49. [62]Zhang B Wang J Wang X Zhu J Liu Q Shi Z Proteogenomic characterization of human colon and rectal cancer Nature. 2014 513 7518 382 387 10.1038/nature13438 25043054 PMC4249766 · DOI · Paper page
  50. [63]Robins C, Wingo AP, Fan W, Duong DM, Meigs J, Gerasimov ES, et al. Genetic control of the human brain proteome. bioRxiv. 2019;816652. 10.1101/816652. · DOI · Paper page
  51. [65]Franceschi C Bonafè M Valensin S Olivieri F Luca MD Ottaviani E Inflamm-aging: an evolutionary perspective on Immunosenescence Ann N Y Acad Sci 2000 908 1 244 254 10.1111/j.1749-6632.2000.tb06651.x 10911963 · DOI · Paper page
  52. [67]Ximerakis M Lipnick SL Innes BT Simmons SK Adiconis X Dionne D Single-cell transcriptomic profiling of the aging mouse brain Nat Neurosci 2019 22 10 1696 1708 10.1038/s41593-019-0491-3 31551601 · DOI · Paper page
  53. [68]Castanho I Murray TK Hannon E Jeffries A Walker E Laing E Transcriptional Signatures of Tau and Amyloid Neuropathology Cell Rep 2020 30 6 2040 2054 10.1016/j.celrep.2020.01.063 32049030 PMC7016505 · DOI · Paper page
  54. [69]Matarin M Salih DA Yasvoina M Cummings DM Guelfi S Liu W A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology Cell Rep 2015 10 4 633 644 10.1016/j.celrep.2014.12.041 25620700 · DOI · Paper page
  55. [71]Lu T Pan Y Kao S-Y Li C Kohane I Chan J Gene regulation and DNA damage in the ageing human brain Nature. 2004 429 6994 883 891 10.1038/nature02661 15190254 · DOI · Paper page
  56. [72]Kunkle BW Grenier-Boley B Sims R Bis JC Damotte V Naj AC Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing Nat Genet 2019 51 3 414 430 10.1038/s41588-019-0358-2 30820047 PMC6463297 · DOI · Paper page
  57. [74]Patrick E, Olah M, Taga M, Klein H-U, Xu J, White CC, et al. A cortical immune network map identifies a subset of human microglia involved in Tau pathology. bioRxiv. 2017;234351. 10.1101/234351. · DOI · Paper page
  58. [76]Yildirim K Petri J Kottmeier R Klämbt C Drosophila glia: few cell types and many conserved functions Glia. 2019 67 1 5 26 10.1002/glia.23459 30443934 · DOI
  59. [77]Davie K Janssens J Koldere D Waegeneer MD Pech U Kreft Ł A Single-Cell Transcriptome Atlas of the Aging Drosophila Brain Cell 2018 174 4 982 998 10.1016/j.cell.2018.05.057 29909982 PMC6086935 · DOI · Paper page
  60. [78]Jansen IE Savage JE Watanabe K Bryois J Williams DM Steinberg S Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk Nat Genet 2019 51 3 404 413 10.1038/s41588-018-0311-9 30617256 PMC6836675 · DOI · Paper page
  61. [79]Chibnik LB White CC Mukherjee S Raj T Yu L Larson EB Susceptibility to neurofibrillary tangles: role of the PTPRD locus and limited pleiotropy with other neuropathologies Mol Psychiatry 2018 23 6 1521 1529 10.1038/mp.2017.20 28322283 PMC5608624 · DOI
  62. [80]Höglinger GU Melhem NM Dickson DW Sleiman PMA Wang L-S Klei L Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy Nat Genet 2011 43 7 699 705 10.1038/ng.859 21685912 PMC3125476 · DOI · Paper page
  63. [81]Bardai FH Wang L Mutreja Y Yenjerla M Gamblin TC Feany MB A conserved cytoskeletal signaling Cascade mediates neurotoxicity of FTDP-17 tau mutations in vivo J Neurosci 2018 38 1 108 119 29138281 PMC5761430

Authors
Mangleburg, C. G., Wu, T., Yalamanchili, H. K., Guo, C., Hsieh, Y.-C., Duong, D. M., Dammer, E. B., De Jager, P. L., Seyfried, N. T., Liu, Z., & Shulman, J. M.
Affiliations
  • Baylor College of Medicine (US)
  • Emory University (US)
Corresponding author
Shulman, Joshua M.
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2020-09-29
Volume
15
Issue
1
Pages
56-56
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-020-00405-4
PMC
PMC7526226
OpenAlex
W3090585201
Cited by
75
References
86
Citations by year
2026: 9 · 2025: 13 · 2024: 21 · 2023: 7 · 2022: 9 · 2021: 15 · 2020: 1
FWCI
4.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Institute on Aging (R01AG053960, R01AG057339, U01AG061357, U01 AG046161)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
tauopathy, neurofibrillary tangles, Alzheimer's disease, frontotemporal dementia, brain transcriptome, brain proteome, aging, Drosophila model, innate immune activation, gene expression networks, neurodegeneration
MeSH terms
Aging, Animals, Brain, Drosophila, Humans, Mutation, tau Proteins, Tauopathies, Transcriptome

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