Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

C/EBPβ/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer’s disease

Molecular Psychiatry volume 27, pages 3034–3046 (2022)Cite this article

Subjects

Abstract

Atherosclerosis (ATH) and Alzheimer’s disease (AD) are both age-dependent inflammatory diseases, associated with infiltrated macrophages and vascular pathology and overlapping molecules. C/EBPβ, an Aβ or inflammatory cytokine-activated transcription factor, and AEP (asparagine endopeptidase) are intimately implicated in both ATH and AD; however, whether C/EBPβ/AEP signaling couples ATH to AD pathogenesis remains incompletely understood. Here we show that C/EBPβ/AEP pathway mediates ATH pathology and couples ATH to AD. Deletion of C/EBPβ or AEP from primary macrophages diminishes cholesterol load, and inactivation of this pathway reduces foam cell formation and lesions in aorta in ApoE−/− mice, fed with HFD (high-fat-diet). Knockout of ApoE from 3xTg AD mouse model augments serum LDL and increases lesion areas in the aorta. Depletion of C/EBPβ or AEP from 3xTg/ApoE−/− mice substantially attenuates these effects and elevates cerebral blood flow and vessel length, improving cognitive functions. Strikingly, knockdown of ApoE from the hippocampus of 3xTg mice decreases the cerebral blood flow and vessel length and aggravates AD pathologies, leading to cognitive deficits. Inactivation of C/EBPβ/AEP pathway alleviates these events and restores cognitive functions. Hence, our findings demonstrate that C/EBPβ/AEP signaling couples ATH to AD via mediating vascular pathology.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Inactivation of C/EBPβ/AEP reduces atherosclerosis in ApoE−/− mice.
Fig. 2: Inactivation of C/EBPβ/AEP signaling attenuates atherosclerosis in 3xTg/ApoE−/− mice.
Fig. 3: C/EBPβ/AEP inactivation attenuates cerebral vascular dysfunction in 3xTg/ApoE−/− mice.
Fig. 4: C/EBPβ/AEP deficiency alleviates cognitive impairment in 3xTg/ApoE KO mice.
Fig. 5: ApoE knockdown activates C/EBPβ/AEP pathway and escalates cerebral vascular dysfunctions in 3xTg mice.
Fig. 6: C/EBPβ/AEP inactivation alleviates ApoE hippocampal deletion-elicited AD pathologies and cognitive function in 3xTg mice.

Similar content being viewed by others

References

  1. Emini Veseli B, Perrotta P, De Meyer GRA, Roth L, Van der Donckt C, Martinet W, et al. Animal models of atherosclerosis. Eur J Pharmacol. 2017;816:3–13.

    Article  CAS  PubMed  Google Scholar 

  2. Hansson GK, Libby P. The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol. 2006;6:508–19.

    Article  CAS  PubMed  Google Scholar 

  3. Sato Y, Watanabe R, Uchiyama N, Ozawa N, Takahashi Y, Shirai R, et al. Inhibitory effects of vasostatin-1 against atherogenesis. Clin Sci. 2018;132:2493–507.

    Article  CAS  Google Scholar 

  4. Lusis AJ. Atherosclerosis. Nature. 2000;407:233–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer’s disease: inflammation, cholesterol, and misfolded proteins. Lancet. 2004;363:1139–46.

    Article  CAS  PubMed  Google Scholar 

  6. Lathe R, Sapronova A, Kotelevtsev Y. Atherosclerosis and Alzheimer—diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatrics. 2014;14:36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Kokjohn TA, Van Vickle GD, Maarouf CL, Kalback WM, Hunter JM, Daugs ID, et al. Chemical characterization of pro-inflammatory amyloid-beta peptides in human atherosclerotic lesions and platelets. Biochim Biophys Acta Mol Basis Dis. 2011;1812:1508–14.

    Article  CAS  Google Scholar 

  8. Li L, Cao D, Garber DW, Kim H, Fukuchi K-I. Association of aortic atherosclerosis with cerebral β-amyloidosis and learning deficits in a mouse model of Alzheimer’s disease. Am J Pathol. 2003;163:2155–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tibolla G, Norata GD, Meda C, Arnaboldi L, Uboldi P, Piazza F, et al. Increased atherosclerosis and vascular inflammation in APP transgenic mice with apolipoprotein E deficiency. Atherosclerosis. 2010;210:78–87.

    Article  CAS  PubMed  Google Scholar 

  10. Van De Parre TJ, Guns PJ, Fransen P, Martinet W, Bult H, Herman AG, et al. Attenuated atherogenesis in apolipoprotein E-deficient mice lacking amyloid precursor protein. Atherosclerosis. 2011;216:54–58.

    Article  CAS  Google Scholar 

  11. Meir KS, Leitersdorf E. Atherosclerosis in the apolipoprotein-E-deficient mouse: a decade of progress. Arterioscler Thromb Vasc Biol. 2004;24:1006–14.

    Article  CAS  PubMed  Google Scholar 

  12. Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988;240:622–30.

    Article  CAS  PubMed  Google Scholar 

  13. Breslow JL. Mouse Models of Atherosclerosis. Science. 1996;272:685.

    Article  CAS  PubMed  Google Scholar 

  14. Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Investig. 1994;93:1885–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N. Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells. Proc Natl Acad Sci USA. 1992;89:4471–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell. 1992;71:343–53.

    Article  CAS  PubMed  Google Scholar 

  17. Silvestre-Roig C, de Winther MP, Weber C, Daemen MJ, Lutgens E, Soehnlein O. Atherosclerotic plaque destabilization: mechanisms, models, and therapeutic strategies. Circulation Res. 2014;114:214–26.

    Article  CAS  PubMed  Google Scholar 

  18. Chen JM, Dando PM, Rawlings ND, Brown MA, Young NE, Stevens RA, et al. Cloning, isolation, and characterization of mammalian legumain, an asparaginyl endopeptidase. J Biol Chem. 1997;272:8090–8.

    Article  CAS  PubMed  Google Scholar 

  19. Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang Z, Song M, Liu X, Su Kang S, Duong DM, Seyfried NT, et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat Commun. 2015;6:8762.

    Article  CAS  PubMed  Google Scholar 

  21. Wu Z, Liu X, Cheng L, Ye K. Delta-secretase triggers Alzheimer’s disease pathologies in wild-type hAPP/hMAPT double transgenic mice. Cell Death Dis. 2020;11:1058.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang Z, Obianyo O, Dall E, Du Y, Fu H, Liu X, et al. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease. Nat Commun. 2017;8:14740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mattock KL, Gough PJ, Humphries J, Burnand K, Patel L, Suckling KE, et al. Legumain and cathepsin-L expression in human unstable carotid plaque. Atherosclerosis. 2010;208:83–89.

    Article  CAS  PubMed  Google Scholar 

  24. Ammirati E, Fogacci F. Clinical relevance of biomarkers for the identification of patients with carotid atherosclerotic plaque: Potential role and limitations of cysteine protease legumain. Atherosclerosis. 2017;257:248–9.

    Article  CAS  PubMed  Google Scholar 

  25. Lunde NN, Holm S, Dahl TB, Elyouncha I, Sporsheim B, Gregersen I, et al. Increased levels of legumain in plasma and plaques from patients with carotid atherosclerosis. Atherosclerosis. 2017;257:216–23.

    Article  CAS  PubMed  Google Scholar 

  26. Ozawa N, Sato Y, Mori Y, Masuda H, Yamane M, Yamamoto Y, et al. Legumain promotes atherosclerotic vascular remodeling. Int J Mol Sci. 2019;20:2195.

  27. Rahman SM, Schroeder-Gloeckler JM, Janssen RC, Jiang H, Qadri I, Maclean KN, et al. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet-induced nonalcoholic steatohepatitis. Hepatology. 2007;45:1108–17.

    Article  CAS  PubMed  Google Scholar 

  28. Schroeder-Gloeckler JM, Rahman SM, Janssen RC, Qiao L, Shao J, Roper M, et al. CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. J Biol Chem. 2007;282:15717–29.

    Article  CAS  PubMed  Google Scholar 

  29. Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nat Commun. 2018;9:1784.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Wang H, Liu X, Chen S, Ye K. Spatiotemporal activation of the C/EBPβ/δ-secretase axis regulates the pathogenesis of Alzheimer’s disease. Proc Natl Acad Sci USA. 2018;115:E12427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zaret KS, Carroll JS. Pioneer transcription factors: establishing competence for gene expression. Genes Dev. 2011;25:2227–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Reddick RL, Zhang SH, Maeda N. Atherosclerosis in mice lacking apo E. Evaluation of lesional development and progression. Arterioscler Thromb. 1994;14:141–7.

    Article  CAS  PubMed  Google Scholar 

  33. Rahman SM, Baquero KC, Choudhury M, Janssen RC, de la Houssaye BA, Sun M, et al. C/EBPβ in bone marrow is essential for diet induced inflammation, cholesterol balance, and atherosclerosis. Atherosclerosis. 2016;250:172–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Poli V. The role of C/EBP isoforms in the control of inflammatory and native immunity functions. J Biol Chem. 1998;273:29279–82.

    Article  CAS  PubMed  Google Scholar 

  35. Wang ZH, Xia Y, Liu P, Liu X, Edgington-Mitchell L, Lei K, et al. ApoE4 activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer’s disease. Prog Neurobiol. 2021;202:102032.

    Article  CAS  PubMed  Google Scholar 

  36. Shirahama-Noda K, Yamamoto A, Sugihara K, Hashimoto N, Asano M, Nishimura M, et al. Biosynthetic processing of cathepsins and lysosomal degradation are abolished in asparaginyl endopeptidase-deficient mice*. J Biol Chem. 2003;278:33194–9.

    Article  CAS  PubMed  Google Scholar 

  37. Zhang X, Goncalves R, Mosser DM. The isolation and characterization of murine macrophages. Curr Protoc Immunol. 2008;83:1–14.

    Article  Google Scholar 

  38. Brown MS, Goldstein JL. Lipoprotein metabolism in the macrophage: implications for cholesterol deposition in atherosclerosis. Annu Rev Biochem. 1983;52:223–61.

    Article  CAS  PubMed  Google Scholar 

  39. Libby P. Inflammation in atherosclerosis. Nature. 2002;420:868–74.

    Article  CAS  PubMed  Google Scholar 

  40. Sterneck E, Tessarollo L, Johnson PF. An essential role for C/EBPbeta in female reproduction. Genes Dev. 1997;11:2153–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gupta A, Iadecola C. Impaired Aβ clearance: a potential link between atherosclerosis and Alzheimer’s disease. Front Aging Neurosci. 2015;7:115.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Roher AE, Esh C, Kokjohn TA, Kalback W, Luehrs DC, Seward JD, et al. Circle of willis atherosclerosis is a risk factor for sporadic Alzheimer’s disease. Arterioscler Thromb Vasc Biol. 2003;23:2055–62.

    Article  CAS  PubMed  Google Scholar 

  43. Getz GS, Reardon CA. ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis. J Lipid Res. 2016;57:758–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Knouff C, Hinsdale ME, Mezdour H, Altenburg MK, Watanabe M, Quarfordt SH, et al. Apo E structure determines VLDL clearance and atherosclerosis risk in mice. J Clin Investig. 1999;103:1579–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zambón D, Quintana M, Mata P, Alonso R, Benavent J, Cruz-Sánchez F, et al. Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med. 2010;123:267–74.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Xia Y, Wang ZH, Zhang J, Liu X, Yu SP, Ye KX, et al. C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer’s disease. Mol Psychiatry. 2020;26:6002–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995;91:2488–96.

    Article  CAS  PubMed  Google Scholar 

  48. Roher AE, Debbins JP, Malek-Ahmadi M, Chen K, Pipe JG, Maze S, et al. Cerebral blood flow in Alzheimer’s disease. Vasc Health Risk Manag. 2012;8:599–611.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Niwa K, Kazama K, Younkin SG, Carlson GA, Iadecola C. Alterations in cerebral blood flow and glucose utilization in mice overexpressing the amyloid precursor protein. Neurobiol Dis. 2002;9:61–8.

    Article  CAS  PubMed  Google Scholar 

  50. Zaghi J, Goldenson B, Inayathullah M, Lossinsky AS, Masoumi A, Avagyan H, et al. Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy. Acta Neuropathol. 2009;117:111–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Lee PH, Bang OY, Hwang EM, Lee JS, Joo US, Mook-Jung I, et al. Circulating beta amyloid protein is elevated in patients with acute ischemic stroke. J Neural Transm. 2005;112:1371–9.

    Article  CAS  PubMed  Google Scholar 

  52. Thomas T, Thomas G, McLendon C, Sutton T, Mullan M. β-Amyloid-mediated vasoactivity and vascular endothelial damage. Nature. 1996;380:168–71.

    Article  CAS  PubMed  Google Scholar 

  53. Townsend K, Obregon D, Quadros A, Patel N, Volmar C, Paris D, et al. Proinflammatory and vasoactive effects of Aβ in the cerebrovasculature. Annals of the New York Academy of Sciences. 2002;977:65–76.

    Article  CAS  PubMed  Google Scholar 

  54. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39:409–21.

    Article  CAS  PubMed  Google Scholar 

  55. Bales KR, Verina T, Cummins DJ, Du Y, Dodel RC, Saura J, et al. Apolipoprotein E is essential for amyloid deposition in the APP(V717F) transgenic mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA. 1999;96:15233–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Fryer JD, Taylor JW, DeMattos RB, Bales KR, Paul SM, Parsadanian M, et al. Apolipoprotein E markedly facilitates age-dependent cerebral amyloid angiopathy and spontaneous hemorrhage in amyloid precursor protein transgenic mice. J Neurosci. 2003;23:7889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Nilsson LN, Arendash GW, Leighty RE, Costa DA, Low MA, Garcia MF, et al. Cognitive impairment in PDAPP mice depends on ApoE and ACT-catalyzed amyloid formation. Neurobiol Aging. 2004;25:1153–67.

    Article  CAS  PubMed  Google Scholar 

  58. Yamada M. Risk factors for cerebral amyloid angiopathy in the elderly. Ann N Y Acad Sci. 2002;977:37–44.

    Article  PubMed  Google Scholar 

  59. Burns MP, Noble WJ, Olm V, Gaynor K, Casey E, LaFrancois J, et al. Co-localization of cholesterol, apolipoprotein E and fibrillar Aβ in amyloid plaques. Mol Brain Res. 2003;110:119–25.

    Article  CAS  PubMed  Google Scholar 

  60. Puglielli L, Friedlich AL, Setchell KD, Nagano S, Opazo C, Cherny RA, et al. Alzheimer disease beta-amyloid activity mimics cholesterol oxidase. J Clin Investig. 2005;115:2556–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Brown AJ, Jessup W. Oxysterols and atherosclerosis. Atherosclerosis. 1999;142:1–28.

    Article  CAS  PubMed  Google Scholar 

  62. Vaya J, Aviram M, Mahmood S, Hayek T, Grenadir E, Hoffman A, et al. Selective distribution of oxysterols in atherosclerotic lesions and human plasma lipoproteins. Free Radic Res. 2001;34:485–97.

    Article  CAS  PubMed  Google Scholar 

  63. van den Kommer TN, Dik MG, Comijs HC, Fassbender K, Lütjohann D, Jonker C. Total cholesterol and oxysterols: Early markers for cognitive decline in elderly? Neurobiol Aging. 2009;30:534–45.

    Article  PubMed  CAS  Google Scholar 

  64. Geifman N, Brinton RD, Kennedy RE, Schneider LS, Butte AJ. Evidence for benefit of statins to modify cognitive decline and risk in Alzheimer’s disease. Alzheimer’s Res Ther. 2017;9:10.

    Article  CAS  Google Scholar 

  65. McGuinness B, Passmore P. Can statins prevent or help treat Alzheimer’s disease? J Alzheimer’s Dis. 2010;20:925–33.

    Article  CAS  Google Scholar 

  66. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis. The ASTEROID Trial. JAMA. 2006;295:1556–65.

    Article  CAS  PubMed  Google Scholar 

  67. Ballantyne CM, Raichlen JS, Nicholls SJ, Erbel R, Tardif JC, Brener SJ, et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation. 2008;117:2458–66.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work is supported by a grant from the National Institute of Health (RO1, AG065177) to KY. This study was supported in part by the Rodent Behavioral Core (RBC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Viral Vector Core of the Emory Neuroscience NINDS Core Facilities (P30NS055077). Further support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378.

Author information

Author notes

  1. These authors contributed equally: Jianming Liao, Guiqin Chen.

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Jianming Liao, Guiqin Chen, Xia Liu & Keqiang Ye

  2. Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

    Jianming Liao & Qianxue Chen

  3. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

    Guiqin Chen

  4. Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, 30322, USA

    Zheng Zachory Wei & Shan Ping Yu

  5. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China

    Keqiang Ye

Authors
  1. Jianming Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Guiqin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zheng Zachory Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shan Ping Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qianxue Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keqiang Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KY conceived the project, designed the experiments, analyzed the data and wrote the manuscript. JL and GC designed and performed most of the experiments and analyzed the data. XL prepared primary macrophages and assisted with in vivo and in vitro experiments. ZZW, SPY and QC assisted with data analysis and interpretation and critically read the manuscript.

Corresponding authors

Correspondence to Qianxue Chen or Keqiang Ye.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liao, J., Chen, G., Liu, X. et al. C/EBPβ/AEP signaling couples atherosclerosis to the pathogenesis of Alzheimer’s disease. Mol Psychiatry 27, 3034–3046 (2022). https://doi.org/10.1038/s41380-022-01556-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41380-022-01556-0

This article is cited by

Search

Advanced search

Quick links