Neurobiochemical, Peptidomic, and Bioinformatic Approaches to Characterize Tauopathy Peptidome Biomarker Candidates in Experimental Mouse Model of Traumatic Brain Injury

Hamad Yadikar 1, Connor Johnson 2, Niko Pafundi 2, Lynn Nguyen 2, Milin Kurup 2, Isabel Torres 2, Albandery Al-Enezy 2, Zhihui Yang 2, Richard Yost 3, Firas H Kobeissy 4 5 6, Kevin K W Wang 7 8 9

Affiliations

04 January 2023

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doi: 10.1007/s12035-022-03165-y

Abstract

Traumatic brain injury (TBI) is a multidimensional damage, and currently, no FDA-approved medicine is available. Multiple pathways in the cell are triggered through a head injury (e.g., calpain and caspase activation), which truncate tau and generate variable fragment sizes (MW 400-45,000 K). In this study, we used an open-head TBI mouse model generated by controlled cortical impact (CCI) and collected ipsilateral (IC) and contralateral (CC) mice htau brain cortices at one (D1) three (D3), and seven (D7) days post-injury. We implemented immunological (antibody-based detection) and peptidomic approaches (nano-reversed-phase liquid chromatography/tandem mass spectrometry) to investigate proteolytic tau peptidome (low molecular weight (LMW) < 10 K)) and pathological phosphorylation sites (high-molecular-weight (HMW); > 10 K) derived from CCI-TBI animal models. Our immunoblotting analysis verified tau hyperphosphorylation, HMW, and HMW breakdown products (HMW-BDP) formation of tau (e.g., pSer202, pThr181, pThr231, pSer396, and pSer404), following CCI-TBI. Peptidomic data revealed unique sequences of injury-dependent proteolytic peptides generated from human tau protein. Among the N-terminal tau peptides, EIPEGTTAEEAGIGDTPSLEDEAAGHVTQA (a.a. 96-125) and AQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARM (a.a. 91-127). Examples of tau C-terminal peptides identified include NVSSTGSIDMVDSPQLATLADEVSASLAKQGL (a.a. 410-441) and QLATLADEVSASLAKQGL (a.a. 424-441). Our peptidomic bioinformatic tools showed the association of proteases, such as CAPN1, CAPN2, and CTSL; CASP1, MMP7, and MMP9; and ELANE, GZMA, and MEP1A, in CCI-TBI tau peptidome. In clinical trials for novel TBI treatments, it might be useful to monitor a subset of tau peptidome as targets for biomarker utility and use them for a "theranostic" approach.

Keywords: CCI; Peptidome Biomarkers; Peptidomics; TBI; Tau phosphorylation; Tauopathy.

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References

  1.  
    1. Blennow K, Brody DL, Kochanek PM, Levin H, McKee A, Ribbers GM, Yaffe K, Zetterberg H (2016) Traumatic brain injuries. Nat Rev Dis Primers 2:16084. https://doi.org/10.1038/nrdp.2016.84 - DOI - PubMed
  2.  
    1. Dewan MC, Rattani A, Gupta S, Baticulon RE, Hung YC, Punchak M, Agrawal A, Adeleye AO, et al (2018) Estimating the global incidence of traumatic brain injury. J Neurosurg:1–18. https://doi.org/10.3171/2017.10.JNS17352
  3.  
    1. McMahon P, Hricik A, Yue JK, Puccio AM, Inoue T, Lingsma HF, Beers SR, Gordon WA et al (2014) Symptomatology and functional outcome in mild traumatic brain injury: results from the prospective TRACK-TBI study. J Neurotrauma 31(1):26–33. https://doi.org/10.1089/neu.2013.2984 - DOI - PubMed - PMC
  4.  
    1. Prins M, Greco T, Alexander D, Giza CC (2013) The pathophysiology of traumatic brain injury at a glance. Dis Model Mech 6(6):1307–1315. https://doi.org/10.1242/dmm.011585 - DOI - PubMed - PMC
  5.  
    1. McKee AC, Daneshvar DH (2015) The neuropathology of traumatic brain injury. Handb Clin Neurol 127:45–66. https://doi.org/10.1016/b978-0-444-52892-6.00004-0 - DOI - PubMed - PMC
  6.  
    1. Xiong Y, Mahmood A, Chopp M (2013) Animal models of traumatic brain injury. Nat Rev Neurosci 14(2):128–142. https://doi.org/10.1038/nrn3407 - DOI - PubMed - PMC
  7.  
    1. Delcourt V, Franck J, Quanico J, Gimeno JP, Wisztorski M, Raffo-Romero A, Kobeissy F, Roucou X et al (2018) Spatially-Resolved top-down proteomics bridged to MALDI MS imaging reveals the molecular physiome of brain regions. Mol Cell Proteomics 17(2):357–372. https://doi.org/10.1074/mcp.M116.065755 - DOI - PubMed
  8.  
    1. Azar S, Hasan A, Younes R, Najdi F, Baki L, Ghazale H, Kobeissy FH, Zibara K et al (2017) Biofluid Proteomics and biomarkers in traumatic brain injury. Methods Mol Biol 1598:45–63. https://doi.org/10.1007/978-1-4939-6952-4_3 - DOI - PubMed
  9.  
    1. Wang KK, Ottens A, Haskins W, Liu MC, Kobeissy F, Denslow N, Chen S, Hayes RL (2004) Proteomics studies of traumatic brain injury. Int Rev Neurobiol 61:215–240. https://doi.org/10.1016/S0074-7742(04)61009-9 - DOI - PubMed
  10.  
    1. Osier N, Dixon CE (2016) The Controlled cortical impact model of experimental brain trauma: overview, research applications, and protocol. Methods Mol Biol 1462:177–192. https://doi.org/10.1007/978-1-4939-3816-2_11 - DOI - PubMed - PMC
  11.  
    1. Abou-Abbass H, Bahmad H, Abou-El-Hassan H, Zhu R, Zhou S, Dong X, Hamade E, Mallah K et al (2016) Deciphering glycomics and neuroproteomic alterations in experimental traumatic brain injury: comparative analysis of aspirin and clopidogrel treatment. Electrophoresis 37(11):1562–1576. https://doi.org/10.1002/elps.201500583 - DOI - PubMed - PMC
  12.  
    1. Kobeissy FH, Guingab-Cagmat JD, Zhang Z, Moghieb A, Glushakova OY, Mondello S, Boutte AM, Anagli J et al (2016) Neuroproteomics and systems biology approach to identify temporal biomarker changes post experimental traumatic brain injury in Rats. Front Neurol 7:198. https://doi.org/10.3389/fneur.2016.00198 - DOI - PubMed - PMC
  13.  
    1. Ando K, Leroy K, Heraud C, Yilmaz Z, Authelet M, Suain V, De Decker R, Brion JP (2011) Accelerated human mutant tau aggregation by knocking out murine tau in a transgenic mouse model. Am J Pathol 178(2):803–816. https://doi.org/10.1016/j.ajpath.2010.10.034 - DOI - PubMed - PMC
  14.  
    1. Lee SW, Jang MS, Jeong SH, Kim H (2019) Exploratory, cognitive, and depressive-like behaviors in adult and pediatric mice exposed to controlled cortical impact. Clin Exp Emerg Med 6(2):125–137. https://doi.org/10.15441/ceem.18.019 - DOI - PubMed - PMC
  15.  
    1. Chodobski A, Zink BJ, Szmydynger-Chodobska J (2011) Blood-brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2(4):492–516. https://doi.org/10.1007/s12975-011-0125-x - DOI - PubMed - PMC
  16.  
    1. Turtzo LC, Budde MD, Gold EM, Lewis BK, Janes L, Yarnell A, Grunberg NE, Watson W et al (2013) The evolution of traumatic brain injury in a rat focal contusion model. NMR Biomed 26(4):468–479. https://doi.org/10.1002/nbm.2886 - DOI - PubMed
  17.  
    1. Rubenstein R, Chang B, Grinkina N, Drummond E, Davies P, Ruditzky M, Sharma D, Wang K et al. (2017) Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein. Acta Neuropathol Commun 5. https://doi.org/10.1186/s40478-017-0435-7
  18.  
    1. Bittar A, Bhatt N, Hasan TF, Montalbano M, Puangmalai N, McAllen S, Ellsworth A, Carretero Murillo M et al (2019) Neurotoxic tau oligomers after single versus repetitive mild traumatic brain injury. Brain Commun 1(1):fcz004. https://doi.org/10.1093/braincomms/fcz004 - DOI - PubMed - PMC
  19.  
    1. Gerson J, Castillo-Carranza DL, Sengupta U, Bodani R, Prough DS, DeWitt DS, Hawkins BE, Kayed R (2016) Tau Oligomers derived from traumatic brain injury cause cognitive impairment and accelerate onset of pathology in htau mice. J Neurotrauma 33(22):2034–2043. https://doi.org/10.1089/neu.2015.4262 - DOI - PubMed - PMC
  20.  
    1. Edwards Iii GA, Zhao J, Dash PK, Soto C, Moreno-Gonzalez I (2019) Traumatic brain injury induces tau aggregation and spreading. J Neurotrauma. https://doi.org/10.1089/neu.2018.6348 - DOI
  21.  
    1. Gabbita SP, Scheff SW, Menard RM, Roberts K, Fugaccia I, Zemlan FP (2005) Cleaved-tau: a biomarker of neuronal damage after traumatic brain injury. J Neurotrauma 22(1):83–94. https://doi.org/10.1089/neu.2005.22.83 - DOI - PubMed
  22.  
    1. Liu MC, Kobeissy F, Zheng W, Zhang Z, Hayes RL, Wang KK (2011) Dual vulnerability of tau to calpains and caspase-3 proteolysis under neurotoxic and neurodegenerative conditions. ASN Neuro 3(1):e00051. https://doi.org/10.1042/AN20100012 - DOI - PubMed
  23.  
    1. Mohamed AZ, Cumming P, Gotz J, Nasrallah F, Department of Defense Alzheimer’s Disease Neuroimaging I (2019) Tauopathy in veterans with long-term posttraumatic stress disorder and traumatic brain injury. Eur J Nucl Med Mol Imaging 46(5):1139–1151. https://doi.org/10.1007/s00259-018-4241-7 - DOI - PubMed - PMC
  24.  
    1. Castellani RJ, Perry G (2019) Tau Biology, tauopathy, traumatic brain injury, and diagnostic challenges. J Alzheimers Dis 67(2):447–467. https://doi.org/10.3233/JAD-180721 - DOI - PubMed - PMC
  25.  
    1. Yadikar H, Torres I, Aiello G, Kurup M, Yang Z, Lin F, Kobeissy F, Yost R et al (2020) Screening of tau protein kinase inhibitors in a tauopathy-relevant cell-based model of tau hyperphosphorylation and oligomerization. PLoS ONE 15(7):e0224952. https://doi.org/10.1371/journal.pone.0224952 - DOI - PubMed - PMC
  26.  
    1. Planel E, Yasutake K, Fujita SC, Ishiguro K (2001) Inhibition of protein phosphatase 2A overrides tau protein kinase I/glycogen synthase kinase 3 beta and cyclin-dependent kinase 5 inhibition and results in tau hyperphosphorylation in the hippocampus of starved mouse. J Biol Chem 276(36):34298–34306. https://doi.org/10.1074/jbc.M102780200 - DOI - PubMed
  27.  
    1. Ng SY, Lee AYW (2019) Traumatic brain injuries: pathophysiology and potential therapeutic targets. Front Cell Neurosci 13:528. https://doi.org/10.3389/fncel.2019.00528 - DOI - PubMed - PMC
  28.  
    1. Chong FP, Ng KY, Koh RY, Chye SM (2018) Tau proteins and tauopathies in Alzheimer’s disease. Cell Mol Neurobiol 38(5):965–980. https://doi.org/10.1007/s10571-017-0574-1 - DOI - PubMed
  29.  
    1. Katsumoto A, Takeuchi H, Tanaka F (2019) Tau pathology in chronic traumatic encephalopathy and Alzheimer’s disease: similarities and differences. Front Neurol 10:980. https://doi.org/10.3389/fneur.2019.00980 - DOI - PubMed - PMC
  30.  
    1. Mutreja Y, Combs B, Gamblin TC (2019) FTDP-17 Mutations alter the aggregation and microtubule stabilization propensity of tau in an isoform-specific fashion. Biochemistry 58(6):742–754. https://doi.org/10.1021/acs.biochem.8b01039 - DOI - PubMed
  31.  
    1. Chang HY, Sang TK, Chiang AS (2018) Untangling the tauopathy for Alzheimer’s disease and parkinsonism. J Biomed Sci 25(1):54. https://doi.org/10.1186/s12929-018-0457-x - DOI - PubMed - PMC
  32.  
    1. Tan CC, Zhang XY, Tan L, Yu JT (2018) Tauopathies: mechanisms and therapeutic strategies. J Alzheimers Dis 61(2):487–508. https://doi.org/10.3233/JAD-170187 - DOI - PubMed
  33.  
    1. Spillantini MG, Bird TD, Ghetti B (1998) Frontotemporal dementia and Parkinsonism linked to chromosome 17: a new group of tauopathies. Brain Pathol 8(2):387–402. https://doi.org/10.1111/j.1750-3639.1998.tb00162.x - DOI - PubMed
  34.  
    1. Smith DH, Uryu K, Saatman KE, Trojanowski JQ, McIntosh TK (2003) Protein accumulation in traumatic brain injury. Neuromolecular Med 4(1–2):59–72. https://doi.org/10.1385/NMM:4:1-2:59 - DOI - PubMed
  35.  
    1. Grady MS, Mclaughlin MR, Christman CW, Valadka AB, Fligner CL, Povlishock JT (1993) The use of antibodies targeted against the neurofilament subunits for the detection of diffuse axonal injury in humans. J Neuropath Exp Neur 52(2):143–152 - DOI - PubMed
  36.  
    1. Johnson VE, Stewart W, Smith DH (2012) Widespread tau and amyloid-beta pathology many years after a single traumatic brain injury in humans. Brain Pathol 22(2):142–149. https://doi.org/10.1111/j.1750-3639.2011.00513.x - DOI - PubMed
  37.  
    1. Limorenko G, Lashuel HA (2022) Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies. Chem Soc Rev 51(2):513–565. https://doi.org/10.1039/d1cs00127b - DOI - PubMed
  38.  
    1. Boyarko B, Hook V (2021) Human tau isoforms and proteolysis for production of toxic tau fragments in neurodegeneration. Front Neurosci 15:702788. https://doi.org/10.3389/fnins.2021.702788 - DOI - PubMed - PMC
  39.  
    1. Quinn JP, Corbett NJ, Kellett KAB, Hooper NM (2018) Tau proteolysis in the pathogenesis of tauopathies: neurotoxic fragments and novel biomarkers. J Alzheimers Dis 63(1):13–33. https://doi.org/10.3233/JAD-170959 - DOI - PubMed - PMC
  40.  
    1. Shoji M (2019) Cerebrospinal fluid and plasma tau as a biomarker for brain tauopathy. Adv Exp Med Biol 1184:393–405. https://doi.org/10.1007/978-981-32-9358-8_29 - DOI - PubMed
  41.  
    1. Di Meo A, Pasic MD, Yousef GM (2016) Proteomics and peptidomics: moving toward precision medicine in urological malignancies. Oncotarget 7(32):52460–52474. https://doi.org/10.18632/oncotarget.8931 - DOI - PubMed - PMC
  42.  
    1. Dallas DC, Guerrero A, Parker EA, Robinson RC, Gan J, German JB, Barile D, Lebrilla CB (2015) Current peptidomics: Applications, purification, identification, quantification, and functional analysis. Proteomics 15:1026–1038. https://doi.org/10.1002/pmic.201400310 - DOI - PubMed - PMC
  43.  
    1. Cunningham R, Ma D, Li L (2012) Mass Spectrometry-based proteomics and peptidomics for systems biology and biomarker discovery. Front Biol (Beijing) 7(4):313–335. https://doi.org/10.1007/s11515-012-1218-y - DOI - PubMed
  44.  
    1. Yin P, Hou X, Romanova EV, Sweedler JV (2011) Neuropeptidomics: mass spectrometry-based qualitative and quantitative analysis. Methods Mol Biol 789:223–236. https://doi.org/10.1007/978-1-61779-310-3_14 - DOI - PubMed - PMC
  45.  
    1. Raad M, El Tal T, Gul R, Mondello S, Zhang Z, Boustany RM, Guingab J, Wang KK et al (2012) Neuroproteomics approach and neurosystems biology analysis: ROCK inhibitors as promising therapeutic targets in neurodegeneration and neurotrauma. Electrophoresis 33(24):3659–3668. https://doi.org/10.1002/elps.201200470 - DOI - PubMed
  46.  
    1. Yadikar H, Sarkis GA, Kurup M, Kobeissy F, Wang KK (2020) Chapter 28 - Peptidomics and traumatic brain injury: biomarker utilities for a theragnostic approach. In: Wu AHB, Peacock WF (eds) Biomarkers for Traumatic Brain Injury. Academic Press, pp 419–430. https://doi.org/10.1016/B978-0-12-816346-7.00028-2
  47.  
    1. Kelley CM, Perez SE, Mufson EJ (2019) Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study. Acta Neuropathol Commun 7(1):207. https://doi.org/10.1186/s40478-019-0861-9 - DOI - PubMed - PMC
  48.  
    1. Agoston DV, Shutes-David A, Peskind ER (2017) Biofluid biomarkers of traumatic brain injury. Brain Inj 31(9):1195–1203. https://doi.org/10.1080/02699052.2017.1357836 - DOI - PubMed
  49.  
    1. Wang KK, Yang Z, Zhu T, Shi Y, Rubenstein R, Tyndall JA, Manley GT (2018) An update on diagnostic and prognostic biomarkers for traumatic brain injury. Expert Rev Mol Diagn 18(2):165–180. https://doi.org/10.1080/14737159.2018.1428089 - DOI - PubMed - PMC
  50.  
    1. Kawata K, Liu CY, Merkel SF, Ramirez SH, Tierney RT, Langford D (2016) Blood biomarkers for brain injury: what are we measuring? Neurosci Biobehav Rev 68:460–473. https://doi.org/10.1016/j.neubiorev.2016.05.009 - DOI - PubMed - PMC
  51.  
    1. El-Hachem N, Haibe-Kains B, Khalil A, Kobeissy FH, Nemer G (2017) AutoDock and AutoDockTools for protein-ligand docking: beta-site amyloid precursor protein cleaving enzyme 1(BACE1) as a case study. Methods Mol Biol 1598:391–403. https://doi.org/10.1007/978-1-4939-6952-4_20 - DOI - PubMed
  52.  
    1. Yu C, Kobeissy F (2015) Systems biology applications to decipher mechanisms and novel biomarkers in CNS trauma. In: Kobeissy FH (ed) Brain neurotrauma: molecular, neuropsychological, and rehabilitation aspects, chap 30. Frontiers in Neuroengineering. CRC Press/Taylor & Francis, Boca Raton (FL)
  53.  
    1. Zetterberg H, Smith DH, Blennow K (2013) Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol 9(4):201–210. https://doi.org/10.1038/nrneurol.2013.9 - DOI - PubMed - PMC
  54.  
    1. Patel PD, Stafflinger JE, Marwitz JH, Niemeier JP, Ottens AK (2021) Secreted Peptides for diagnostic trajectory assessments in brain injury rehabilitation. Neurorehabil Neural Repair 35(2):169–184. https://doi.org/10.1177/1545968320975428 - DOI - PubMed
  55.  
    1. Ottens AK, Stafflinger JE, Griffin HE, Kunz RD, Cifu DX, Niemeier JP (2014) Post-acute brain injury urinary signature: a new resource for molecular diagnostics. J Neurotrauma 31(8):782–788. https://doi.org/10.1089/neu.2013.3116 - DOI - PubMed - PMC
  56.  
    1. Lakshmanan R, Loo JA, Drake T, Leblanc J, Ytterberg AJ, McArthur DL, Etchepare M, Vespa PM (2010) Metabolic crisis after traumatic brain injury is associated with a novel microdialysis proteome. Neurocrit Care 12(3):324–336 - DOI - PubMed - PMC
  57.  
    1. Yang ZH, Zhu T, Mondello S, Akel M, Wong AT, Kothari IM, Lin F, Shear DA et al (2019) Serum-based phospho-neurofilament-heavy protein as theranostic biomarker in three models of traumatic brain injury: an operation brain trauma therapy study. J Neurotraum 36(2):348–359 - DOI
  58.  
    1. Yadikar H, Johnson C, Pafundi N, Mouhawasse E, Nguyen L, Torres I, Kurup M, Yang Z, et al. (2019) Novel Peptidomic approach for identification of low and high molecular weight tauopathy peptides following calpain digestion, and primary culture neurotoxic challenges. Int J Mol Sci 20(20). https://doi.org/10.3390/ijms20205213
  59.  
    1. Sarkis GA, Lees-Gayed N, Banoub J, Abbatielo SE, Robertson C, Haskins WE, Yost RA, Wang KKW (2021) Generation and release of neurogranin, vimentin, and MBP proteolytic peptides, following traumatic brain injury. Mol Neurobiol. https://doi.org/10.1007/s12035-021-02600-w - DOI - PubMed
  60.  
    1. Manguy J, Jehl P, Dillon ET, Davey NE, Shields DC, Holton TA (2017) Peptigram: a web-based application for peptidomics data visualization. J Proteome Res 16(2):712–719. https://doi.org/10.1021/acs.jproteome.6b00751 - DOI - PubMed
  61.  
    1. Klein J, Eales J, Zurbig P, Vlahou A, Mischak H, Stevens R (2013) Proteasix: a tool for automated and large-scale prediction of proteases involved in naturally occurring peptide generation. Proteomics 13(7):1077–1082. https://doi.org/10.1002/pmic.201200493 - DOI - PubMed
  62.  
    1. Song J, Tan H, Perry AJ, Akutsu T, Webb GI, Whisstock JC, Pike RN (2012) PROSPER: an integrated feature-based tool for predicting protease substrate cleavage sites. PLoS ONE 7(11):e50300. https://doi.org/10.1371/journal.pone.0050300 - DOI - PubMed - PMC
  63.  
    1. Kobeissy FH, Liu MC, Yang Z, Zhang Z, Zheng W, Glushakova O, Mondello S, Anagli J et al (2015) Degradation of betaII-spectrin protein by calpain-2 and caspase-3 under neurotoxic and traumatic brain injury conditions. Mol Neurobiol 52(1):696–709. https://doi.org/10.1007/s12035-014-8898-z - DOI - PubMed
  64.  
    1. Liu S, Yin F, Zhang J, Qian Y (2014) The role of calpains in traumatic brain injury. Brain Inj 28(2):133–137. https://doi.org/10.3109/02699052.2013.860479 - DOI - PubMed
  65.  
    1. Lin G, Chai J, Yuan S, Mai C, Cai L, Murphy RW, Zhou W, Luo J (2016) VennPainter: a tool for the comparison and identification of candidate genes based on Venn diagrams. PLoS ONE 11(4):e0154315. https://doi.org/10.1371/journal.pone.0154315 - DOI - PubMed - PMC
  66.  
    1. Schulz-Knappe P, Schrader M, Zucht HD (2005) The peptidomics concept. Comb Chem High Throughput Screen 8(8):697–704. https://doi.org/10.2174/138620705774962418 - DOI - PubMed
  67.  
    1. Wijte D, McDonnell LA, Balog CI, Bossers K, Deelder AM, Swaab DF, Verhaagen J, Mayboroda OA (2012) A novel peptidomics approach to detect markers of Alzheimer’s disease in cerebrospinal fluid. Methods 56(4):500–507. https://doi.org/10.1016/j.ymeth.2012.03.018 - DOI - PubMed
  68.  
    1. Cafe-Mendes CC, Ferro ES, Britto LRG, Martins-de-Souza D (2014) Using Mass spectrometry-based peptidomics to understand the brain and disorders such as Parkinson’s disease and schizophrenia. Curr Top Med Chem 14(3):369–381 - DOI - PubMed
  69.  
    1. Brondani LA, Soares AA, Recamonde-Mendoza M, Dall’Agnol A, Camargo JL, Monteiro KM, Silveiro SP (2020) Urinary peptidomics and bioinformatics for the detection of diabetic kidney disease. Sci Rep 10(1):1242. https://doi.org/10.1038/s41598-020-58067-7 - DOI - PubMed - PMC
  70.  
    1. Crutchfield CA, Thomas SN, Sokoll LJ, Chan DW (2016) Advances in mass spectrometry-based clinical biomarker discovery. Clin Proteomics 13:1. https://doi.org/10.1186/s12014-015-9102-9 - DOI - PubMed - PMC
  71.  
    1. Nudo RJ (2003) Adaptive plasticity in motor cortex: implications for rehabilitation after brain injury. J Rehabil Med (41 Suppl):7–10. https://doi.org/10.1080/16501960310010070
  72.  
    1. Carron SF, Alwis DS, Rajan R (2016) Traumatic Brain injury and neuronal functionality changes in sensory cortex. Front Syst Neurosci 10:47. https://doi.org/10.3389/fnsys.2016.00047 - DOI - PubMed - PMC
  73.  
    1. Lee M, Reddy H, Johansen-Berg H, Pendlebury S, Jenkinson M, Smith S, Palace J, Matthews PM (2000) The motor cortex shows adaptive functional changes to brain injury from multiple sclerosis. Ann Neurol 47(5):606–613 - DOI - PubMed
  74.  
    1. Raghavendra Rao VL, Dhodda VK, Song G, Bowen KK, Dempsey RJ (2003) Traumatic brain injury-induced acute gene expression changes in rat cerebral cortex identified by GeneChip analysis. J Neurosci Res 71(2):208–219. https://doi.org/10.1002/jnr.10486 - DOI - PubMed
  75.  
    1. Chen ZH, Wang H, Zhong JJ, Yang JQ, Darwazeh R, Tian XC, Huang ZJ, Jiang L et al (2019) Significant changes in circular RNA in the mouse cerebral cortex around an injury site after traumatic brain injury. Exp Neurol 313:37–48 - DOI - PubMed
  76.  
    1. Yao XL, Liu J, Lee E, Ling GS, McCabe JT (2005) Progesterone differentially regulates pro- and anti-apoptotic gene expression in cerebral cortex following traumatic brain injury in rats. J Neurotrauma 22(6):656–668. https://doi.org/10.1089/neu.2005.22.656 - DOI - PubMed
  77.  
    1. Kobori N, Clifton GL, Dash P (2002) Altered expression of novel genes in the cerebral cortex following experimental brain injury. Brain Res Mol Brain Res 104(2):148–158. https://doi.org/10.1016/s0169-328x(02)00331-5 - DOI - PubMed
  78.  
    1. Nilsson P, Hillered L, Ponten U, Ungerstedt U (1990) Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10(5):631–637. https://doi.org/10.1038/jcbfm.1990.115 - DOI - PubMed
  79.  
    1. Alwis DS, Yan EB, Morganti-Kossmann MC, Rajan R (2012) Sensory cortex underpinnings of traumatic brain injury deficits. PLoS ONE 7(12):e52169. https://doi.org/10.1371/journal.pone.0052169 - DOI - PubMed - PMC
  80.  
    1. Merkley TL, Bigler ED, Wilde EA, McCauley SR, Hunter JV, Levin HS (2008) Diffuse changes in cortical thickness in pediatric moderate-to-severe traumatic brain injury. J Neurotrauma 25(11):1343–1345. https://doi.org/10.1089/neu.2008.0615 - DOI - PubMed - PMC
  81.  
    1. Wilde EA, Merkley TL, Bigler ED, Max JE, Schmidt AT, Ayoub KW, McCauley SR, Hunter JV et al (2012) Longitudinal changes in cortical thickness in children after traumatic brain injury and their relation to behavioral regulation and emotional control. Int J Dev Neurosci 30(3):267–276. https://doi.org/10.1016/j.ijdevneu.2012.01.003 - DOI - PubMed - PMC
  82.  
    1. Bramlett HM, Dietrich WD (2002) Quantitative structural changes in white and gray matter 1 year following traumatic brain injury in rats. Acta Neuropathol 103(6):607–614. https://doi.org/10.1007/s00401-001-0510-8 - DOI - PubMed
  83.  
    1. Rola R, Mizumatsu S, Otsuka S, Morhardt DR, Noble-Haeusslein LJ, Fishman K, Potts MB, Fike JR (2006) Alterations in hippocampal neurogenesis following traumatic brain injury in mice. Exp Neurol 202(1):189–199. https://doi.org/10.1016/j.expneurol.2006.05.034 - DOI - PubMed
  84.  
    1. Baskaya MK, Rao AM, Dogan A, Donaldson D, Dempsey RJ (1997) The biphasic opening of the blood-brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci Lett 226(1):33–36. https://doi.org/10.1016/s0304-3940(97)00239-5 - DOI - PubMed
  85.  
    1. Pischiutta F, Micotti E, Hay JR, Marongiu I, Sammali E, Tolomeo D, Vegliante G, Stocchetti N et al (2018) Single severe traumatic brain injury produces progressive pathology with ongoing contralateral white matter damage one year after injury. Exp Neurol 300:167–178. https://doi.org/10.1016/j.expneurol.2017.11.003 - DOI - PubMed
  86.  
    1. Aungst SL, Kabadi SV, Thompson SM, Stoica BA, Faden AI (2014) Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits. J Cereb Blood Flow Metab 34(7):1223–1232. https://doi.org/10.1038/jcbfm.2014.75 - DOI - PubMed - PMC
  87.  
    1. Zhao X, Ahram A, Berman RF, Muizelaar JP, Lyeth BG (2003) Early loss of astrocytes after experimental traumatic brain injury. Glia 44(2):140–152. https://doi.org/10.1002/glia.10283 - DOI - PubMed
  88.  
    1. Zhuo JC, Xu S, Proctor JL, Mullins RJ, Simon JZ, Fiskum G, Gullapalli RP (2012) Diffusion kurtosis as an in vivo imaging marker for reactive astrogliosis in traumatic brain injury. Neuroimage 59(1):467–477 - DOI - PubMed
  89.  
    1. Zanier ER, Bertani I, Sammali E, Pischiutta F, Chiaravalloti MA, Vegliante G, Masone A, Corbelli A et al (2018) Induction of a transmissible tau pathology by traumatic brain injury. Brain 141:2685–2699 - PubMed - PMC
  90.  
    1. Rubenstein R, Sharma DR, Chang B, Oumata N, Cam M, Vaucelle L, Lindberg MF, Chiu A et al (2019) Novel mouse tauopathy model for repetitive mild traumatic brain injury: evaluation of long-term effects on cognition and biomarker levels after therapeutic inhibition of tau phosphorylation. Front Neurol 10:124. https://doi.org/10.3389/fneur.2019.00124 - DOI - PubMed - PMC
  91.  
    1. Bright J, Hussain S, Dang V, Wright S, Cooper B, Byun T, Ramos C, Singh A et al (2015) Human secreted tau increases amyloid-beta production. Neurobiol Aging 36(2):693–709. https://doi.org/10.1016/j.neurobiolaging.2014.09.007 - DOI - PubMed
  92.  
    1. Petry FR, Pelletier J, Bretteville A, Morin F, Calon F, Hebert SS, Whittington RA, Planel E (2014) Specificity of anti-tau antibodies when analyzing mice models of Alzheimer’s disease: problems and solutions. PLoS ONE 9(5):e94251. https://doi.org/10.1371/journal.pone.0094251 - DOI - PubMed - PMC
  93.  
    1. Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM (2011) Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem 118(4):658–667. https://doi.org/10.1111/j.1471-4159.2011.07337.x - DOI - PubMed - PMC
  94.  
    1. Ferguson SA, Mouzon BC, Lynch C, Lungmus C, Morin A, Crynen G, Carper B, Bieler G et al (2017) Negative Impact of female sex on outcomes from repetitive mild traumatic brain injury in htau mice is age dependent: a chronic effects of neurotrauma consortium study. Front Aging Neurosci 9:416. https://doi.org/10.3389/fnagi.2017.00416 - DOI - PubMed - PMC
  95.  
    1. Guo T, Noble W, Hanger DP (2017) Roles of tau protein in health and disease. Acta Neuropathol 133(5):665–704. https://doi.org/10.1007/s00401-017-1707-9 - DOI - PubMed - PMC
  96.  
    1. Hawkins BE, Krishnamurthy S, Castillo-Carranza DL, Sengupta U, Prough DS, Jackson GR, DeWitt DS, Kayed R (2013) Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathieS*. J Biol Chem 288(23):17042–17050. https://doi.org/10.1074/jbc.M113.472746 - DOI - PubMed - PMC
  97.  
    1. Kimura T, Sharma G, Ishiguro K, Hisanaga SI (2018) Phospho-tau bar code: analysis of phosphoisotypes of tau and its application to tauopathy. Front Neurosci 12:44. https://doi.org/10.3389/fnins.2018.00044 - DOI - PubMed - PMC
  98.  
    1. Rubenstein R, Chang B, Yue JK, Chiu A, Winkler EA, Puccio AM, Diaz-Arrastia R, Yuh EL et al (2017) Comparing plasma phospho tau, total tau, and phospho tau-total tau ratio as acute and chronic traumatic brain injury biomarkers. JAMA Neurol 74(9):1063–1072. https://doi.org/10.1001/jamaneurol.2017.0655 - DOI - PubMed - PMC
  99.  
    1. Alonso AD, Di Clerico J, Li B, Corbo CP, Alaniz ME, Grundke-Iqbal I, Iqbal K (2010) Phosphorylation of tau at Thr212, Thr231, and Ser262 combined causes neurodegeneration. J Biol Chem 285(40):30851–30860. https://doi.org/10.1074/jbc.M110.110957 - DOI - PubMed - PMC
  100.  
    1. Moszczynski AJ, Strong W, Xu K, McKee A, Brown A, Strong MJ (2018) Pathologic Thr175 tau phosphorylation in CTE and CTE with ALS. Neurology 90(5):e380-387. https://doi.org/10.1212/wnl.0000000000004899 - DOI - PubMed - PMC
  101.  
    1. Nakamura K, Greenwood A, Binder L, Bigio EH, Denial S, Nicholson L, Zhou XZ, Lu KP (2012) Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer’s disease. Cell 149(1):232–244. https://doi.org/10.1016/j.cell.2012.02.016 - DOI - PubMed - PMC
  102.  
    1. Götz J, Gladbach A, Pennanen L, van Eersel J, Schild A, David D, Ittner LM (2010) Animal models reveal role for tau phosphorylation in human disease. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1802(10):860–871. https://doi.org/10.1016/j.bbadis.2009.09.008 - DOI - PubMed
  103.  
    1. Hanger DP, Byers HL, Wray S, Leung KY, Saxton MJ, Seereeram A, Reynolds CH, Ward MA et al (2007) Novel phosphorylation sites in tau from Alzheimer brain support a role for casein kinase 1 in disease pathogenesis. J Biol Chem 282(32):23645–23654. https://doi.org/10.1074/jbc.M703269200 - DOI - PubMed
  104.  
    1. Janelidze S, Stomrud E, Smith R, Palmqvist S, Mattsson N, Airey DC, Proctor NK, Chai XY, Shcherbinin S, Sims JR, Triana-Baltzer G, Theunis C, Slemmon R, Mercken M, Kolb H, Dage JL, Hansson O (2020) Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer’s disease. Nat Commun 11(1):1683
  105.  
    1. Triana-Baltzer G, Van Kolen K, Theunis C, Moughadam S, Slemmon R, Mercken M, Galpern W, Sun H et al (2020) Development and validation of a high sensitivity assay for measuring p217+tau in cerebrospinal fluid. Journal of Alzheimers Disease 77(4):1417–1430 - DOI
  106.  
    1. Jicha GA, O’Donnell A, Weaver C, Angeletti R, Davies P (1999) Hierarchical phosphorylation of recombinant tau by the paired-helical filament-associated protein kinase is dependent on cyclic AMP-dependent protein kinase. J Neurochem 72(1):214–224 - DOI - PubMed
  107.  
    1. Congdon EE, Sigurdsson EM (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14(7):399–415. https://doi.org/10.1038/s41582-018-0013-z - DOI - PubMed - PMC
  108.  
    1. Gyparaki MT, Arab A, Sorokina EM, Santiago-Ruiz AN, Bohrer CH, Xiao J, Lakadamyali M (2021) Tau forms oligomeric complexes on microtubules that are distinct from tau aggregates. Proc Natl Acad Sci USA 118(19):e2021461118. https://doi.org/10.1073/pnas.2021461118
  109.  
    1. Oakley SS, Maina MB, Marshall KE, Al-Hilaly YK, Harrington CR, Wischik CM, Serpell LC (2020) Tau Filament Self-Assembly and Structure: Tau as a Therapeutic Target. Front Neurol 11:590754. https://doi.org/10.3389/fneur.2020.590754 - DOI - PubMed - PMC
  110.  
    1. Kanaan NM, Hamel C, Grabinski T, Combs B (2020) Liquid-liquid phase separation induces pathogenic tau conformations in vitro. Nat Commun 11(1):2809. https://doi.org/10.1038/s41467-020-16580-3 - DOI - PubMed - PMC
  111.  
    1. Hawkins BE, Krishnamurthy S, Castillo-Carranza DL, Sengupta U, Prough DS, Jackson GR, DeWitt DS, Kayed R (2013) Rapid accumulation of endogenous tau oligomers in a rat model of traumatic brain injury: possible link between traumatic brain injury and sporadic tauopathies*. In: J Biol Chem 288(23):17042–17050. https://doi.org/10.1074/jbc.M113.472746 - DOI - PubMed - PMC
  112.  
    1. Newcomb JK, Kampfl A, Posmantur RM, Zhao X, Pike BR, Liu SJ, Clifton GL, Hayes RL (1997) Immunohistochemical study of calpain-mediated breakdown products to alpha-spectrin following controlled cortical impact injury in the rat. J Neurotrauma 14(6):369–383. https://doi.org/10.1089/neu.1997.14.369 - DOI - PubMed
  113.  
    1. Wang KK, Posmantur R, Nath R, McGinnis K, Whitton M, Talanian RV, Glantz SB, Morrow JS (1998) Simultaneous degradation of alphaII- and betaII-spectrin by caspase 3 (CPP32) in apoptotic cells. J Biol Chem 273(35):22490–22497. https://doi.org/10.1074/jbc.273.35.22490 - DOI - PubMed
  114.  
    1. Pike BR, Flint J, Dutta S, Johnson E, Wang KK, Hayes RL (2001) Accumulation of non-erythroid alpha II-spectrin and calpain-cleaved alpha II-spectrin breakdown products in cerebrospinal fluid after traumatic brain injury in rats. J Neurochem 78(6):1297–1306 - DOI - PubMed
  115.  
    1. Pineda JA, Lewis SB, Valadka AB, Papa L, Hannay HJ, Heaton SC, Demery JA, Liu MC et al (2007) Clinical significance of alphaII-spectrin breakdown products in cerebrospinal fluid after severe traumatic brain injury. J Neurotrauma 24(2):354–366. https://doi.org/10.1089/neu.2006.003789 - DOI - PubMed
  116.  
    1. Pike BR, Flint J, Dave JR, Lu XCM, Wang KKK, Tortella FC, Hayes RL (2004) Accumulation of calpain and caspase-3 proteolytic fragments of brain-derived alpha II-spectrin in cerebral spinal fluid after middle cerebral artery occlusion in rats. J Cerebr Blood F Met 24(1):98–106 - DOI
  117.  
    1. Wang KK, Ottens AK, Liu MC, Lewis SB, Meegan C, Oli MW, Tortella FC, Hayes RL (2005) Proteomic identification of biomarkers of traumatic brain injury. Expert Rev Proteomics 2(4):603–614. https://doi.org/10.1586/14789450.2.4.603 - DOI - PubMed
  118.  
    1. Chi H, Sun L, Shiu RH, Han R, Hsieh CP, Wei TM, Lo CC, Chang HY et al (2020) Cleavage of human tau at Asp421 inhibits hyperphosphorylated tau induced pathology in a Drosophila model. Sci Rep 10(1):13482. https://doi.org/10.1038/s41598-020-70423-1 - DOI - PubMed - PMC
  119.  
    1. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y et al (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci U S A 100(17):10032–10037. https://doi.org/10.1073/pnas.1630428100 - DOI - PubMed - PMC
  120.  
    1. Kim B, Backus C, Oh S, Feldman EL (2013) Hyperglycemia-induced tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer’s disease. J Alzheimers Dis 34(3):727–739. https://doi.org/10.3233/jad-121669 - DOI - PubMed - PMC
  121.  
    1. Dolan PJ, Johnson GVW (2010) A caspase cleaved form of tau is preferentially degraded through the autophagy pathway*. J Biol Chem 285(29):21978–21987. https://doi.org/10.1074/jbc.M110.110940 - DOI - PubMed - PMC
  122.  
    1. Flores-Rodriguez P, Ontiveros-Torres MA, Cardenas-Aguayo MC, Luna-Arias JP, Meraz-Rios MA, Viramontes-Pintos A, Harrington CR, Wischik CM et al (2015) The relationship between truncation and phosphorylation at the C-terminus of tau protein in the paired helical filaments of Alzheimer’s disease. Front Neurosci 9:33. https://doi.org/10.3389/fnins.2015.00033 - DOI - PubMed - PMC
  123.  
    1. Mondragon-Rodriguez S, Mena R, Binder LI, Smith MA, Perry G, Garcia-Sierra F (2008) Conformational changes and cleavage of tau in Pick bodies parallel the early processing of tau found in Alzheimer pathology. Neuropathol Appl Neurobiol 34(1):62–75. https://doi.org/10.1111/j.1365-2990.2007.00853.x - DOI - PubMed
  124.  
    1. Jarero-Basulto JJ, Luna-Munoz J, Mena R, Kristofikova Z, Ripova D, Perry G, Binder LI, Garcia-Sierra F (2013) Proteolytic cleavage of polymeric tau protein by caspase-3: implications for Alzheimer disease. J Neuropathol Exp Neurol 72(12):1145–1161. https://doi.org/10.1097/nen.0000000000000013 - DOI - PubMed
  125.  
    1. Ma X, Aravind A, Pfister BJ, Chandra N, Haorah J (2019) Animal models of traumatic brain injury and assessment of injury severity. Mol Neurobiol 56(8):5332–5345. https://doi.org/10.1007/s12035-018-1454-5 - DOI - PubMed
  126.  
    1. Cole JT, Yarnell A, Kean WS, Gold E, Lewis B, Ren M, McMullen DC, Jacobowitz DM et al (2011) Craniotomy: true sham for traumatic brain injury, or a sham of a sham? J Neurotrauma 28(3):359–369. https://doi.org/10.1089/neu.2010.1427 - DOI - PubMed - PMC
  127.  
    1. Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K, Wojtkiewicz GR, Masson GS et al (2018) Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci 21(9):1209–1217. https://doi.org/10.1038/s41593-018-0213-2 - DOI - PubMed - PMC
  128.  
    1. Louveau A, Plog BA, Antila S, Alitalo K, Nedergaard M, Kipnis J (2017) Understanding the functions and relationships of the glymphatic system and meningeal lymphatics. J Clin Invest 127(9):3210–3219. https://doi.org/10.1172/JCI90603 - DOI - PubMed - PMC
  129.  
    1. Yang LS, Ksiezak-Reding H (1995) Calpain-induced proteolysis of normal human tau and tau associated with paired helical filaments. Eur J Biochem 233(1):9–17. https://doi.org/10.1111/j.1432-1033.1995.009_1.x - DOI - PubMed
  130.  
    1. Park SY, Ferreira A (2005) The generation of a 17 kDa neurotoxic fragment: an alternative mechanism by which tau mediates beta-amyloid-induced neurodegeneration. J Neurosci 25(22):5365–5375. https://doi.org/10.1523/JNEUROSCI.1125-05.2005 - DOI - PubMed - PMC
  131.  
    1. Matsumoto SE, Motoi Y, Ishiguro K, Tabira T, Kametani F, Hasegawa M, Hattori N (2015) The twenty-four KDa C-terminal tau fragment increases with aging in tauopathy mice: implications of prion-like properties. Hum Mol Genet 24(22):6403–6416. https://doi.org/10.1093/hmg/ddv351 - DOI - PubMed
  132.  
    1. Garg S, Timm T, Mandelkow EM, Mandelkow E, Wang Y (2011) Cleavage of Tau by calpain in Alzheimer’s disease: the quest for the toxic 17 kD fragment. Neurobiol Aging 32(1):1–14. https://doi.org/10.1016/j.neurobiolaging.2010.09.008 - DOI - PubMed
  133.  
    1. Ferreira A, Bigio EH (2011) Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med 17(7–8):676–685. https://doi.org/10.2119/molmed.2010.00220 - DOI - PubMed - PMC
  134.  
    1. Chesser AS, Pritchard SM, Johnson GVW (2013) Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease. Front Neurol 4:122
  135.  
    1. Derisbourg M, Leghay C, Chiappetta G, Fernandez-Gomez FJ, Laurent C, Demeyer D, Carrier S, Buee-Scherrer V et al (2015) Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci Rep 5:9659. https://doi.org/10.1038/srep09659 - DOI - PubMed - PMC
  136.  
    1. Wilgus TA, Roy S, McDaniel JC (2013) Neutrophils and Wound Repair: Positive Actions and Negative Reactions. Adv Wound Care (New Rochelle) 2(7):379–388. https://doi.org/10.1089/wound.2012.0383 - DOI - PubMed - PMC
  137.  
    1. Stoka V, Turk V, Turk B (2016) Lysosomal cathepsins and their regulation in aging and neurodegeneration. Ageing Res Rev 32:22–37. https://doi.org/10.1016/j.arr.2016.04.010 - DOI - PubMed
  138.  
    1. Bednarski E, Lynch G (1996) Cytosolic proteolysis of tau by cathepsin D in hippocampus following suppression of cathepsins B and L. J Neurochem 67(5):1846–1855. https://doi.org/10.1046/j.1471-4159.1996.67051846.x - DOI - PubMed
  139.  
    1. Palmer JT, Bryant C, Wang DX, Davis DE, Setti EL, Rydzewski RM, Venkatraman S, Tian ZQ et al (2005) Design and synthesis of tri-ring P-3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K. J Med Chem 48(24):7520–7534 - DOI - PubMed
  140.  
    1. Shi X, Zhang Y (2020) A humanized antibody inhibitor for cathepsin L. Protein Sci 29(9):1924–1930. https://doi.org/10.1002/pro.3913 - DOI - PubMed - PMC
  141.  
    1. Alvarez-Arce A, Lee-Rivera I, Lopez E, Hernandez-Cruz A, Lopez-Colome AM (2017) Thrombin-induced calpain activation promotes protease-activated receptor 1 internalization. Int J Cell Biol 2017:1908310. https://doi.org/10.1155/2017/1908310 - DOI - PubMed - PMC
  142.  
    1. Hanna RA, Campbell RL, Davies PL (2008) Calcium-bound structure of calpain and its mechanism of inhibition by calpastatin. Nature 456(7220):409–412. https://doi.org/10.1038/nature07451 - DOI - PubMed
  143.  
    1. Stevens T, Ekholm K, Granse M, Lindahl M, Kozma V, Jungar C, Ottosson T, Falk-Hakansson H et al (2011) AZD9668: pharmacological characterization of a novel oral inhibitor of neutrophil elastase. J Pharmacol Exp Ther 339(1):313–320. https://doi.org/10.1124/jpet.111.182139 - DOI - PubMed
  144.  
    1. Wayne GJ, Deng SJ, Amour A, Borman S, Matico R, Carter HL, Murphy G (2007) TIMP-3 inhibition of ADAMTS-4 (Aggrecanase-1) is modulated by interactions between aggrecan and the C-terminal domain of ADAMTS-4. J Biol Chem 282(29):20991–20998 - DOI - PubMed
  145.  
    1. Sananes A, Cohen I, Shahar A, Hockla A, De Vita E, Miller AK, Radisky ES, Papo N (2018) A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering. J Biol Chem 293(33):12663–12680. https://doi.org/10.1074/jbc.RA117.000871 - DOI - PubMed - PMC
  146.  
    1. Chen DZ, Patel DV, Hackbarth CJ, Wang W, Dreyer G, Young DC, Margolis PS, Wu C et al (2000) Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor. Biochemistry 39(6):1256–1262 - DOI - PubMed
  147.  
    1. Niehaus JZ, Miedel MT, Good M, Wyatt AN, Pak SC, Silverman GA, Luke CJ (2015) SERPINB12 is a slow-binding inhibitor of granzyme A and hepsin. Biochemistry 54(45):6756–6759 - DOI - PubMed
  148.  
    1. Winer A, Adams S, Mignatti P (2018) Matrix Metalloproteinase inhibitors in cancer therapy: turning past failures into future successes. Mol Cancer Ther 17(6):1147–1155 - DOI - PubMed - PMC
  149.  
    1. Jin Y, Roycik MD, Bosco DB, Cao Q, Constantino MH, Schwartz MA, Sang QX (2013) Matrix metalloproteinase inhibitors based on the 3-mercaptopyrrolidine core. J Med Chem 56(11):4357–4373. https://doi.org/10.1021/jm400529f - DOI - PubMed - PMC
  150.  
    1. Farace E, Alves WM (2000) Do women fare worse? A metaanalysis of gender differences in outcome after traumatic brain injury. Neurosurg Focus 8(1):e6. https://doi.org/10.3171/foc.2000.8.1.152 - DOI - PubMed
  151.  
    1. Mebrahtu-Ghebrehiwet M, Quan L, Andebirhan T (2009) The profile of CT scan findings in acute head trauma in Orotta Hospital, Asmara, Eritrea. J Eritrean Med Assoc 4(1):5–8
  152.  
    1. Gururaj G (2004) The effect of alcohol on incidence, pattern, severity and outcome from traumatic brain injury. J Indian Med Assoc 102(3):157–160, 163 - PubMed
  153.  
    1. Corrigan JD, Wolfe M, Mysiw WJ, Jackson RD, Bogner JA (2003) Early identification of mild traumatic brain injury in female victims of domestic violence. Am J Obstet Gynecol 188(5 Suppl):S71-76. https://doi.org/10.1067/mob.2003.404 - DOI - PubMed
  154.  
    1. Gerber MR, Iverson KM, Dichter ME, Klap R, Latta RE (2014) Women veterans and intimate partner violence: current state of knowledge and future directions. J Womens Health (Larchmt) 23(4):302–309. https://doi.org/10.1089/jwh.2013.4513 - DOI - PubMed
  155.  
    1. Doust YV, Bindoff A, Holloway OG, Wilson R, King AE, Ziebell JM (2022) Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label-free quantitative proteomics. bioRxiv:2022.2005.2001.490239. https://doi.org/10.1101/2022.05.01.490239

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