Skip to main content

Advertisement

Springer Nature Link
Log in

From Analysis of Ischemic Mouse Brain Proteome to Identification of Human Serum Clusterin as a Potential Biomarker for Severity of Acute Ischemic Stroke

  • Original Article
  • Published:
Translational Stroke Research Aims and scope Submit manuscript

Abstract

Ischemic stroke is a devastating neurological disease that can cause permanent brain damage, but to date, few biomarkers are available to reliably assess the severity of injury during acute onset. In this study, quantitative proteomic analysis of ischemic mouse brain detected the increase in expression levels of clusterin (CLU) and cystatin C (CST3). Since CLU is a secretary protein, serum samples (n = 70) were obtained from acute ischemic stroke (AIS) patients within 24 h of stroke onset and together with 70 matched health controls. Analysis of CLU levels indicated significantly higher levels in AIS patients than healthy controls (14.91 ± 4.03 vs. 12.79 ± 2.22 ng/L; P = 0.0004). Analysis of serum CST3 also showed significant increase in AIS patients as compared with healthy controls (0.90 ± 0.19 vs. 0.84 ± 0.12 ng/L; P = 0.0064). The serum values of CLU were also positively correlated with the NIH Stroke Scale (NIHSS) scores, the time interval after stroke onset, as well as major stroke risk factors associated with lipid profile. These data demonstrate that elevated levels of serum CLU and CST3 are independently associated with AIS and may serve as peripheral biomarkers to aid clinical assessment of AIS and its severity. This pilot study thus contributes to progress toward preclinical proteomic screening by using animal models and allows translation of results from bench to bedside.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. van der Worp HB, van Gijn J. Clinical practice. Acute ischemic stroke. N Engl J Med. 2007;357(6):572–9. https://doi.org/10.1056/NEJMcp072057.

    Article  PubMed  Google Scholar 

  2. Sacco RL, Kasner SE, Broderick JP, Caplan LR, Connors JJ, Culebras A, et al. An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(7):2064–89. https://doi.org/10.1161/STR.0b013e318296aeca.

    Article  PubMed  Google Scholar 

  3. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–322. https://doi.org/10.1161/CIR.0000000000000152.

    Article  PubMed  Google Scholar 

  4. Catanese L, Tarsia J, Fisher M. Acute ischemic stroke therapy overview. Circ Res. 2017;120(3):541–58. https://doi.org/10.1161/CIRCRESAHA.116.309278.

    Article  CAS  PubMed  Google Scholar 

  5. Whiteley W, Chong WL, Sengupta A, Sandercock P. Blood markers for the prognosis of ischemic stroke: a systematic review. Stroke. 2009;40(5):e380–9. https://doi.org/10.1161/STROKEAHA.108.528752.

    Article  PubMed  Google Scholar 

  6. Jickling GC, Sharp FR. Biomarker panels in ischemic stroke. Stroke. 2015;46(3):915–20. https://doi.org/10.1161/STROKEAHA.114.005604.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Maas MB, Furie KL. Molecular biomarkers in stroke diagnosis and prognosis. Biomark Med. 2009;3(4):363–83. https://doi.org/10.2217/bmm.09.30.

    Article  CAS  PubMed  Google Scholar 

  8. Carpenter KL, Czosnyka M, Jalloh I, Newcombe VF, Helmy A, Shannon RJ, et al. Systemic, local, and imaging biomarkers of brain injury: more needed, and better use of those already established? Front Neurol. 2015;6:26. https://doi.org/10.3389/fneur.2015.00026.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lindsey ML, Mayr M, Gomes AV, Delles C, Arrell DK, Murphy AM, et al. Transformative impact of proteomics on cardiovascular health and disease: a scientific statement from the American Heart Association. Circulation. 2015;132(9):852–72. https://doi.org/10.1161/CIR.0000000000000226.

    Article  CAS  PubMed  Google Scholar 

  10. Ning M, Lo EH. Opportunities and challenges in omics. Transl Stroke Res. 2010;1(4):233–7. https://doi.org/10.1007/s12975-010-0048-y.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ning M, Lopez M, Cao J, Buonanno FS, Lo EH. Application of proteomics to cerebrovascular disease. Electrophoresis. 2012;33(24):3582–97. https://doi.org/10.1002/elps.201200481.

    Article  CAS  PubMed  Google Scholar 

  12. Swan AL, Mobasheri A, Allaway D, Liddell S, Bacardit J. Application of machine learning to proteomics data: classification and biomarker identification in postgenomics biology. OMICS. 2013;17(12):595–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zimmermann-Ivol CG, Burkhard PR, Le Floch-Rohr J, Allard L, Hochstrasser DF, Sanchez JC. Fatty acid binding protein as a serum marker for the early diagnosis of stroke: a pilot study. Mol Cell Proteomics. 2004;3(1):66–72. https://doi.org/10.1074/mcp.M300066-MCP200.

    Article  CAS  PubMed  Google Scholar 

  14. Ning M, Sarracino DA, Kho AT, Guo S, Lee SR, Krastins B, et al. Proteomic temporal profile of human brain endothelium after oxidative stress. Stroke. 2011;42(1):37–43. https://doi.org/10.1161/STROKEAHA.110.585703.

    Article  CAS  PubMed  Google Scholar 

  15. Garcia-Berrocoso T, Penalba A, Boada C, Giralt D, Cuadrado E, Colome N, et al. From brain to blood: new biomarkers for ischemic stroke prognosis. J Proteome. 2013;94:138–48. https://doi.org/10.1016/j.jprot.2013.09.005.

    Article  CAS  Google Scholar 

  16. Ramsubramaniam N, Tao F, Li S, Marten MR. Cost-effective isobaric tagging for quantitative phosphoproteomics using DiART reagents. Mol BioSyst. 2013;9(12):2981–7. https://doi.org/10.1039/c3mb70358d.

    Article  CAS  PubMed  Google Scholar 

  17. Ramsubramaniam N, Tao F, Li S, Marten MR. Novel and cost-effective 6-plex isobaric tagging reagent, DiART, is effective for identification and relative quantification of complex protein mixtures using PQD fragmentation. J Mass Spectrom. 2013;48(9):1032–41. https://doi.org/10.1002/jms.3249.

    Article  CAS  PubMed  Google Scholar 

  18. Weinstein G, Beiser AS, Preis SR, Courchesne P, Chouraki V, Levy D, et al. Plasma clusterin levels and risk of dementia, Alzheimer’s disease, and stroke. Alzheimers Dement (Amst). 2016;3:103–9. https://doi.org/10.1016/j.dadm.2016.06.005.

    Article  Google Scholar 

  19. Cevik O, Baykal AT, Sener A. Platelets proteomic profiles of acute ischemic stroke patients. PLoS One. 2016;11(6):e0158287. https://doi.org/10.1371/journal.pone.0158287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Deming Y, Xia J, Cai Y, Lord J, Holmans P, Bertelsen S, et al. A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin. Neurobiol Aging. 2016;37:208 e1–9. https://doi.org/10.1016/j.neurobiolaging.2015.09.009.

    Article  CAS  Google Scholar 

  21. Coll E, Botey A, Alvarez L, Poch E, Quinto L, Saurina A, et al. Serum cystatin C as a new marker for noninvasive estimation of glomerular filtration rate and as a marker for early renal impairment. Am J Kidney Dis. 2000;36(1):29–34. https://doi.org/10.1053/ajkd.2000.8237.

    Article  CAS  PubMed  Google Scholar 

  22. Ni L, Lu J, Hou LB, Yan JT, Fan Q, Hui R, et al. Cystatin C, associated with hemorrhagic and ischemic stroke, is a strong predictor of the risk of cardiovascular events and death in Chinese. Stroke. 2007;38(12):3287–8. https://doi.org/10.1161/STROKEAHA.107.489625.

    Article  CAS  PubMed  Google Scholar 

  23. Fang Z, Deng J, Wu Z, Dong B, Wang S, Chen X, et al. Cystatin C is a crucial endogenous protective determinant against stroke. Stroke. 2017;48(2):436–44. https://doi.org/10.1161/STROKEAHA.116.014975.

    Article  CAS  PubMed  Google Scholar 

  24. Chuang DY, Cui J, Simonyi A, Engel VA, Chen S, Fritsche KL et al. Dietary Sutherlandia and elderberry mitigate cerebral ischemia-induced neuronal damage and attenuate p47phox and phospho-ERK1/2 expression in microglial cells. ASN Neuro. 2014;6(6). https://doi.org/10.1177/1759091414554946.

  25. Johnson MC, Song H, Cui J, Mossine VV, Gu Z, Greenlief CM. Development of a method and validation for the quantitation of FruArg in mice plasma and brain tissue using UPLC–MS/MS. ACS Omega. 2016;1(4):663–8. https://doi.org/10.1021/acsomega.6b00220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Qu Z, Meng F, Bomgarden RD, Viner RI, Li J, Rogers JC, et al. Proteomic quantification and site-mapping of S-nitrosylated proteins using isobaric iodoTMT reagents. J Proteome Res. 2014;13(7):3200–11. https://doi.org/10.1021/pr401179v.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Demaerschalk BM, Kleindorfer DO, Adeoye OM, Demchuk AM, Fugate JE, Grotta JC, et al. Scientific rationale for the inclusion and exclusion criteria for intravenous alteplase in acute ischemic stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2016;47(2):581–641.

    Article  PubMed  Google Scholar 

  28. Lyden PD, Lu M, Levine SR, Brott TG, Broderick J, Group NrSS. A modified National Institutes of Health Stroke Scale for use in stroke clinical trials: preliminary reliability and validity. Stroke. 2001;32(6):1310–7.

    Article  CAS  PubMed  Google Scholar 

  29. Miyake H, Muramaki M, Furukawa J, Kurahashi T, Fujisawa M. Serum level of clusterin and its density in men with prostate cancer as novel biomarkers reflecting disease extension. Urology. 2010;75(2):454–9. https://doi.org/10.1016/j.urology.2009.08.029.

    Article  PubMed  Google Scholar 

  30. Shimizu-Tokiwa A, Kobata M, Io H, Kobayashi N, Shou I, Funabiki K, et al. Serum cystatin C is a more sensitive marker of glomerular function than serum creatinine. Nephron. 2002;92(1):224–6.

    Article  CAS  PubMed  Google Scholar 

  31. Wang J, Jin H, Hua Y, Keep RF, Xi G. Role of protease-activated receptor-1 in brain injury after experimental global cerebral ischemia. Stroke. 2012;43(9):2476–82. https://doi.org/10.1161/STROKEAHA.112.661819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kristian T, Hu B. Guidelines for using mouse global cerebral ischemia models. Transl Stroke Res. 2013;4(3):343–50. https://doi.org/10.1007/s12975-012-0236-z.

    Article  PubMed  Google Scholar 

  33. Chen Z, Wang Q, Lin L, Tang Q, Edwards JL, Li S, et al. Comparative evaluation of two isobaric labeling tags, DiART and iTRAQ. Anal Chem. 2012;84(6):2908–15. https://doi.org/10.1021/ac203467q.

    Article  CAS  PubMed  Google Scholar 

  34. Song H, Lu Y, Qu Z, Mossine VV, Martin MB, Hou J, et al. Effects of aged garlic extract and FruArg on gene expression and signaling pathways in lipopolysaccharide-activated microglial cells. Sci Rep. 2016;6:35323. https://doi.org/10.1038/srep35323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C, et al. Integration of biological networks and gene expression data using Cytoscape. Nat Protoc. 2007;2(10):2366–82. https://doi.org/10.1038/nprot.2007.324.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Arrell DK, Terzic A. Network systems biology for drug discovery. Clin Pharmacol Ther. 2010;88(1):120–5. https://doi.org/10.1038/clpt.2010.91.

    Article  CAS  PubMed  Google Scholar 

  37. Jauch EC WK, Carrozzella J. Proteomic analyses demonstrates ultra-early elevations of inflammation-sensitive plasma proteins following ischemic stroke. 5th World Stroke Congress, Vancouver BC, Canada. 2004.

  38. Jensen MB, Chacon MR, Sattin JA, Aleu A, Lyden PD. The promise and potential pitfalls of serum biomarkers for ischemic stroke and transient ischemic attack. Neurologist. 2008;14(4):243–6. https://doi.org/10.1097/NRL.0b013e31815a9945.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chow SL, Maisel AS, Anand I, Bozkurt B, De Boer RA, Felker GM, et al. Role of biomarkers for the prevention, assessment, and management of heart failure: a scientific statement from the American Heart Association. Circulation. 2017;135(22):e1054–e91.

    Article  CAS  PubMed  Google Scholar 

  40. Zoubeidi A, Chi K, Gleave M. Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clin Cancer Res. 2010;16(4):1088–93. https://doi.org/10.1158/1078-0432.CCR-09-2917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Imhof A, Charnay Y, Vallet PG, Aronow B, Kovari E, French LE, et al. Sustained astrocytic clusterin expression improves remodeling after brain ischemia. Neurobiol Dis. 2006;22(2):274–83. https://doi.org/10.1016/j.nbd.2005.11.009.

    Article  CAS  PubMed  Google Scholar 

  42. Desikan RS, Thompson WK, Holland D, Hess CP, Brewer JB, Zetterberg H, et al. The role of clusterin in amyloid-beta-associated neurodegeneration. JAMA Neurol. 2014;71(2):180–7. https://doi.org/10.1001/jamaneurol.2013.4560.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Santilli G, Aronow BJ, Sala A. Essential requirement of apolipoprotein J (clusterin) signaling for IkappaB expression and regulation of NF-kappaB activity. J Biol Chem. 2003;278(40):38214–9. https://doi.org/10.1074/jbc.C300252200.

    Article  CAS  PubMed  Google Scholar 

  44. Zhang H, Kim JK, Edwards CA, Xu Z, Taichman R, Wang CY. Clusterin inhibits apoptosis by interacting with activated Bax. Nat Cell Biol. 2005;7(9):909–15. https://doi.org/10.1038/ncb1291.

    Article  CAS  PubMed  Google Scholar 

  45. Wehrli P, Charnay Y, Vallet P, Zhu G, Harmony J, Aronow B, et al. Inhibition of post-ischemic brain injury by clusterin overexpression. Nat Med. 2001;7(9):977–9. https://doi.org/10.1038/nm0901-977.

    Article  CAS  PubMed  Google Scholar 

  46. Han BH, DeMattos RB, Dugan LL, Kim-Han JS, Brendza RP, Fryer JD, et al. Clusterin contributes to caspase-3-independent brain injury following neonatal hypoxia-ischemia. Nat Med. 2001;7(3):338–43. https://doi.org/10.1038/85487.

    Article  CAS  PubMed  Google Scholar 

  47. Kroksveen AC, Aasebo E, Vethe H, Van Pesch V, Franciotta D, Teunissen CE, et al. Discovery and initial verification of differentially abundant proteins between multiple sclerosis patients and controls using iTRAQ and SID-SRM. J Proteome. 2013;78:312–25. https://doi.org/10.1016/j.jprot.2012.09.037.

    Article  CAS  Google Scholar 

  48. Tu C, Beharry KD, Shen X, Li J, Wang L, Aranda JV, et al. Proteomic profiling of the retinas in a neonatal rat model of oxygen-induced retinopathy with a reproducible ion-current-based MS1 approach. J Proteome Res. 2015;14(5):2109–20. https://doi.org/10.1021/pr501238m.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Turk V, Turk B, Guncar G, Turk D, Kos J. Lysosomal cathepsins: structure, role in antigen processing and presentation, and cancer. Adv Enzym Regul. 2002;42:285–303.

    Article  CAS  Google Scholar 

  50. Yan S, Sloane BF. Molecular regulation of human cathepsin B: implication in pathologies. Biol Chem. 2003;384(6):845–54. https://doi.org/10.1515/BC.2003.095.

    Article  CAS  PubMed  Google Scholar 

  51. Hakansson K, Huh C, Grubb A, Karlsson S, Abrahamson M. Mouse and rat cystatin C: Escherichia coli production, characterization and tissue distribution. Comp Biochem Physiol B Biochem Mol Biol. 1996;114(3):303–11.

    Article  CAS  PubMed  Google Scholar 

  52. Hoke M, Amighi J, Mlekusch W, Schlager O, Exner M, Sabeti S, et al. Cystatin C and the risk for cardiovascular events in patients with asymptomatic carotid atherosclerosis. Stroke. 2010;41(4):674–9. https://doi.org/10.1161/STROKEAHA.109.573162.

    Article  CAS  PubMed  Google Scholar 

  53. Huang GX, Ji XM, Ding YC, Huang HY. Association between serum cystatin C levels and the severity or potential risk factors of acute ischemic stroke. Neurol Res. 2016;38(6):518–23. https://doi.org/10.1080/01616412.2016.1187825.

    Article  CAS  PubMed  Google Scholar 

  54. Yin GN, Lee HW, Cho JY, Suk K. Neuronal pentraxin receptor in cerebrospinal fluid as a potential biomarker for neurodegenerative diseases. Brain Res. 2009;1265:158–70. https://doi.org/10.1016/j.brainres.2009.01.058.

    Article  CAS  PubMed  Google Scholar 

  55. Martins-de-Souza D, Guest PC, Harris LW, Vanattou-Saifoudine N, Webster MJ, Rahmoune H, et al. Identification of proteomic signatures associated with depression and psychotic depression in post-mortem brains from major depression patients. Transl Psychiatry. 2012;2:e87. https://doi.org/10.1038/tp.2012.13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dr. Jin-Moo Lee of Washington University in St. Louis for scientific comments and Mr. Garrett Ungerer for editing of the manuscript.

Funding Sources

This work is partially supported by a research fund from the Department of Pathology and Anatomical Sciences at the University of Missouri-Columbia (MU) (ZG) and by a grant from the National Institutes of Health National Center for Complementary and Integrative Health (P50AT006273) to the MU Center for Botanical Interaction Studies. The content is solely the responsibility of the authors and does not necessarily represent the official view of the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Pathology & Anatomical Sciences, University of Missouri, Columbia, MO, 65211, USA

    Hailong Song, Hui Zhou, Zhe Qu, Dennis Y. Chuang, Shanyan Chen, Grace Y. Sun, Jiankun Cui & Zezong Gu

  2. Center for Botanical Interaction Studies, University of Missouri, Columbia, MO, 65211, USA

    Hailong Song, Hui Zhou, Zhe Qu, Jie Hou, Dennis Y. Chuang, Shanyan Chen, Jilong Li, Jianlin Cheng, Agnes Simonyi, Grace Y. Sun, Jiankun Cui & Zezong Gu

  3. Computer Science, University of Missouri, Columbia, MO, 65211, USA

    Jie Hou, Jilong Li & Jianlin Cheng

  4. Department of Neurology, the Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine, Fuzhou, 350001, China

    Weilong Chen, Weiwu Cai & Chenghan Wu

  5. Department of Neurology, Fujian Provincial Hospital, Fuzhou, 350001, China

    Qiong Cheng

  6. Biochemistry, University of Missouri, Columbia, MO, 65211, USA

    Dennis Y. Chuang, Agnes Simonyi & Grace Y. Sun

  7. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD, 20742, USA

    Shuwei Li

  8. Chemistry, University of Missouri, Columbia, MO, 65211, USA

    C. Michael Greenlief

  9. Xiphophorus Genetic Stock Center, Texas State University, San Marcos, TX, 78666, USA

    Yuan Lu

Authors
  1. Hailong Song
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hui Zhou
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Zhe Qu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Jie Hou
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Weilong Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Weiwu Cai
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Qiong Cheng
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Dennis Y. Chuang
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Shanyan Chen
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Shuwei Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Jilong Li
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Jianlin Cheng
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. C. Michael Greenlief
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Yuan Lu
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Agnes Simonyi
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Grace Y. Sun
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Chenghan Wu
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Jiankun Cui
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Zezong Gu
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Zezong Gu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Statement of Human Rights/Statement on the Welfare of Animals

Ethical approval for human rights: “All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”

Ethical Approval for the Welfare of Animals

“All procedures performed in studies involving animals were in accordance with the ethical standards of the University of Missouri approved protocols for the Care and Use of Laboratory Animals at which the studies were conducted.”

Informed consent

“Informed consent was obtained from all individual participants included in the study.”

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Hailong Song and Hui Zhou are co-first authors.

Electronic Supplementary Material

ESM 1

(PDF 1286 kb)

Supplementary Table 1

(XLSX 4633 kb)

Supplementary Table 2

(XLSX 4512 kb)

Supplementary Table 3

(XLSX 4319 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Song, H., Zhou, H., Qu, Z. et al. From Analysis of Ischemic Mouse Brain Proteome to Identification of Human Serum Clusterin as a Potential Biomarker for Severity of Acute Ischemic Stroke. Transl. Stroke Res. 10, 546–556 (2019). https://doi.org/10.1007/s12975-018-0675-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12975-018-0675-2

Keywords