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Volumn 33, Issue 1, 2013, Pages 334-343

Specific inhibition of p25/Cdk5 activity by the Cdk5 inhibitory peptide reduces neurodegeneration in vivo

Author keywords

[No Author keywords available]

Indexed keywords

ALPHA TUBULIN; AMYLOID; CYCLIN DEPENDENT KINASE 5; DOXYCYCLINE; PROTEIN P25; TAU PROTEIN;

EID: 84871744906     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.3593-12.2013     Document Type: Article
Times cited : (77)

References (48)
  • 2
    • 0036470547 scopus 로고    scopus 로고
    • Cyclin-dependent kinase 5 (cdk5) activation requires interaction with three domains of p35
    • CrossRef Medline
    • Amin ND, Albers W, Pant HC (2002) Cyclin-dependent kinase 5 (cdk5) activation requires interaction with three domains of p35. J Neurosci Res 67:354-362. CrossRef Medline
    • (2002) J Neurosci Res , vol.67 , pp. 354-362
    • Amin, N.D.1    Albers, W.2    Pant, H.C.3
  • 3
    • 3042641182 scopus 로고    scopus 로고
    • In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI
    • CrossRef Medline
    • Aoki I, Wu YJ, Silva AC, Lynch RM, Koretsky AP (2004) In vivo detection of neuroarchitecture in the rodent brain using manganese-enhanced MRI. Neuroimage 22:1046-1059. CrossRef Medline
    • (2004) Neuroimage , vol.22 , pp. 1046-1059
    • Aoki, I.1    Wu, Y.J.2    Silva, A.C.3    Lynch, R.M.4    Koretsky, A.P.5
  • 5
    • 33644802027 scopus 로고    scopus 로고
    • Improved neuronal tract tracing using manganese enhanced magnetic resonance imaging with fast T(1) mapping
    • CrossRef Medline
    • Chuang KH, Koretsky A (2006) Improved neuronal tract tracing using manganese enhanced magnetic resonance imaging with fast T(1) mapping. Magn Reson Med 55:604-611. CrossRef Medline
    • (2006) Magn Reson Med , vol.55 , pp. 604-611
    • Chuang, K.H.1    Koretsky, A.2
  • 6
    • 4444262625 scopus 로고    scopus 로고
    • Cdk5 deregulation in the pathogenesis of Alzheimer's disease
    • CrossRef Medline
    • Cruz JC, Tsai LH (2004) Cdk5 deregulation in the pathogenesis of Alzheimer's disease. Trends Mol Med 10:452-458. CrossRef Medline
    • (2004) Trends Mol Med , vol.10 , pp. 452-458
    • Cruz, J.C.1    Tsai, L.H.2
  • 7
    • 0345405447 scopus 로고    scopus 로고
    • Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles
    • CrossRef Medline
    • Cruz JC, Tseng HC, Goldman JA, Shih H, Tsai LH (2003) Aberrant Cdk5 activation by p25 triggers pathological events leading to neurodegeneration and neurofibrillary tangles. Neuron 40:471-483. CrossRef Medline
    • (2003) Neuron , vol.40 , pp. 471-483
    • Cruz, J.C.1    Tseng, H.C.2    Goldman, J.A.3    Shih, H.4    Tsai, L.H.5
  • 8
    • 33749826587 scopus 로고    scopus 로고
    • P25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo
    • CrossRef Medline
    • Cruz JC, Kim D, Moy LY, Dobbin MM, Sun X, Bronson RT, Tsai LH (2006) p25/cyclin-dependent kinase 5 induces production and intraneuronal accumulation of amyloid β in vivo. J Neurosci 26:10536-10541. CrossRef Medline
    • (2006) J Neurosci , vol.26 , pp. 10536-10541
    • Cruz, J.C.1    Kim, D.2    Moy, L.Y.3    Dobbin, M.M.4    Sun, X.5    Bronson, R.T.6    Tsai, L.H.7
  • 9
    • 79953198258 scopus 로고    scopus 로고
    • Cyclin-dependent kinase 5 promotes pancreatic beta-cell survival via Fak-Akt signaling pathways
    • CrossRef Medline
    • Daval M, Gurlo T, Costes S, Huang CJ, Butler PC (2011) Cyclin-dependent kinase 5 promotes pancreatic beta-cell survival via Fak-Akt signaling pathways. Diabetes 60:1186-1197. CrossRef Medline
    • (2011) Diabetes , vol.60 , pp. 1186-1197
    • Daval, M.1    Gurlo, T.2    Costes, S.3    Huang, C.J.4    Butler, P.C.5
  • 10
    • 0035489777 scopus 로고    scopus 로고
    • A decade of CDK5
    • CrossRef Medline
    • Dhavan R, Tsai LH (2001) A decade of CDK5. Nat Rev Mol Cell Biol 2:749-759. CrossRef Medline
    • (2001) Nat Rev Mol Cell Biol , vol.2 , pp. 749-759
    • Dhavan, R.1    Tsai, L.H.2
  • 11
    • 0036942843 scopus 로고    scopus 로고
    • Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration
    • CrossRef Medline
    • Ferrer I, Barrachina M, Puig B (2002) Glycogen synthase kinase-3 is associated with neuronal and glial hyperphosphorylated tau deposits in Alzheimer's disease, Pick's disease, progressive supranuclear palsy and corticobasal degeneration. Acta Neuropathol 104:583-591. CrossRef Medline
    • (2002) Acta Neuropathol , vol.104 , pp. 583-591
    • Ferrer, I.1    Barrachina, M.2    Puig, B.3
  • 12
    • 0442276554 scopus 로고    scopus 로고
    • The glamour and gloom of glycogen synthase kinase-3
    • CrossRef Medline
    • Jope RS, Johnson GV (2004) The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci 29:95-102. CrossRef Medline
    • (2004) Trends Biochem Sci , vol.29 , pp. 95-102
    • Jope, R.S.1    Johnson, G.V.2
  • 13
    • 0034805169 scopus 로고    scopus 로고
    • The levels of cdk5 and p35 proteins and tau phosphorylation are reduced during neuronal apoptosis
    • CrossRef Medline
    • Kerokoski P, Suuronen T, Salminen A, Soininen H, Pirttil ä T (2001) The levels of cdk5 and p35 proteins and tau phosphorylation are reduced during neuronal apoptosis. Biochem Biophys Res Commun 280:998-1002. CrossRef Medline
    • (2001) Biochem Biophys Res Commun , vol.280 , pp. 998-1002
    • Kerokoski, P.1    Suuronen, T.2    Salminen, A.3    Soininen, H.4    Pirttilä, T.5
  • 14
    • 1542269015 scopus 로고
    • Neuronal cyclin-dependent kinase 5: Role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide
    • CrossRef Medline
    • Kesavapany S, Li BS, Amin N, Zheng YL, Grant P, Pant HC (2004) Neuronal cyclin-dependent kinase 5: role in nervous system function and its specific inhibition by the Cdk5 inhibitory peptide. Biochim Biophys Acta 1697: 143-153. CrossRef Medline
    • (1697) Biochim Biophys Acta , pp. 143-153
    • Kesavapany, S.1    Li, B.S.2    Amin, N.3    Zheng, Y.L.4    Grant, P.5    Pant6
  • 15
    • 34548480683 scopus 로고    scopus 로고
    • Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5
    • CrossRef Medline
    • Kesavapany S, Zheng YL, Amin N, Pant HC (2007) Peptides derived from Cdk5 activator p35, specifically inhibit deregulated activity of Cdk5. Biotechnol J 2:978-987. CrossRef Medline
    • (2007) Biotechnol J , vol.2 , pp. 978-987
    • Kesavapany, S.1    Zheng, Y.L.2    Amin, N.3    Pant, H.C.4
  • 16
    • 0036926420 scopus 로고    scopus 로고
    • Cdk5 as a drug target for the treatment of Alzheimer's disease
    • CrossRef Medline
    • Lau LF, Seymour PA, Sanner MA, Schachter JB (2002) Cdk5 as a drug target for the treatment of Alzheimer's disease. J Mol Neurosci 19:267-273. CrossRef Medline
    • (2002) J Mol Neurosci , vol.19 , pp. 267-273
    • Lau, L.F.1    Seymour, P.A.2    Sanner, M.A.3    Schachter, J.B.4
  • 17
    • 0035808457 scopus 로고    scopus 로고
    • Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors?
    • CrossRef Medline
    • Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL, Greengard P, Biernat J, Wu YZ, Mandelkow EM, Eisenbrand G, Meijer L (2001) Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer's disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 276:251-260. CrossRef Medline
    • (2001) J Biol Chem , vol.276 , pp. 251-260
    • Leclerc, S.1    Garnier, M.2    Hoessel, R.3    Marko, D.4    Bibb, J.A.5    Snyder, G.L.6    Greengard, P.7    Biernat, J.8    Wu, Y.Z.9    Mandelkow, E.M.10    Eisenbrand, G.11    Meijer, L.12
  • 18
    • 0034682414 scopus 로고    scopus 로고
    • Neurotoxicity induces cleavage of p35 to p25 by calpain
    • CrossRef Medline
    • Lee MS, Kwon YT, Li M, Peng J, Friedlander RM, Tsai LH (2000) Neurotoxicity induces cleavage of p35 to p25 by calpain. Nature 405:360-364. CrossRef Medline
    • (2000) Nature , vol.405 , pp. 360-364
    • Lee, M.S.1    Kwon, Y.T.2    Li, M.3    Peng, J.4    Friedlander, R.M.5    Tsai, L.H.6
  • 21
    • 0035146522 scopus 로고    scopus 로고
    • New temperature modification makes the Bielschowsky silver stain reproducible
    • CrossRef Medline
    • Litchfield S, Nagy Z (2001) New temperature modification makes the Bielschowsky silver stain reproducible. Acta Neuropathol 101:17-21. CrossRef Medline
    • (2001) Acta Neuropathol , vol.101 , pp. 17-21
    • Litchfield, S.1    Nagy, Z.2
  • 22
    • 3042634127 scopus 로고    scopus 로고
    • A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons
    • CrossRef Medline
    • Morfini G, Szebenyi G, Brown H, Pant HC, Pigino G, DeBoer S, Beffert U, Brady ST (2004) A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons. EMBO J 23:2235-2245. CrossRef Medline
    • (2004) EMBO J , vol.23 , pp. 2235-2245
    • Morfini, G.1    Szebenyi, G.2    Brown, H.3    Pant, H.C.4    Pigino, G.5    Deboer, S.6    Beffert, U.7    Brady, S.T.8
  • 23
    • 39549093321 scopus 로고    scopus 로고
    • Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: A model for hippocampal sclerosis and neocortical degeneration
    • CrossRef Medline
    • Muyllaert D, Terwel D, Kremer A, Sennvik K, Borghgraef P, Devijver H, Dewachter I, Van Leuven F (2008) Neurodegeneration and neuroinflammation in cdk5/p25-inducible mice: a model for hippocampal sclerosis and neocortical degeneration. Am J Pathol 172:470-485. CrossRef Medline
    • (2008) Am J Pathol , vol.172 , pp. 470-485
    • Muyllaert, D.1    Terwel, D.2    Kremer, A.3    Sennvik, K.4    Borghgraef, P.5    Devijver, H.6    Dewachter, I.7    van Leuven, F.8
  • 24
    • 0033915457 scopus 로고    scopus 로고
    • Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells
    • CrossRef Medline
    • Nath R, Davis M, Probert AW, Kupina NC, Ren X, Schielke GP, Wang KK (2000) Processing of cdk5 activator p35 to its truncated form (p25) by calpain in acutely injured neuronal cells. Biochem Biophys Res Commun 274:16-21. CrossRef Medline
    • (2000) Biochem Biophys Res Commun , vol.274 , pp. 16-21
    • Nath, R.1    Davis, M.2    Probert, A.W.3    Kupina, N.C.4    Ren, X.5    Schielke, G.P.6    Wang, K.K.7
  • 25
    • 0346119136 scopus 로고    scopus 로고
    • Cyclin-dependent kinase 5 in amyotrophic lateral sclerosis
    • CrossRef Medline
    • Nguyen MD, Julien JP (2003) Cyclin-dependent kinase 5 in amyotrophic lateral sclerosis. Neurosignals 12:215-220. CrossRef Medline
    • (2003) Neurosignals , vol.12 , pp. 215-220
    • Nguyen, M.D.1    Julien, J.P.2
  • 28
    • 33749521100 scopus 로고    scopus 로고
    • Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation
    • CrossRef Medline
    • Oakley H, Cole SL, Logan S, Maus E, Shao P, Craft J, Guillozet-Bongaarts A, Ohno M, Disterhoft J, Van Eldik L, Berry R, Vassar R (2006) Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26:10129-10140. CrossRef Medline
    • (2006) J Neurosci , vol.26 , pp. 10129-10140
    • Oakley, H.1    Cole, S.L.2    Logan, S.3    Maus, E.4    Shao, P.5    Craft, J.6    Guillozet-Bongaarts, A.7    Ohno, M.8    Disterhoft, J.9    van Eldik, L.10    Berry, R.11    Vassar, R.12
  • 30
    • 0033540060 scopus 로고    scopus 로고
    • Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration
    • CrossRef Medline
    • Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH (1999) Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature 402:615-622. CrossRef Medline
    • (1999) Nature , vol.402 , pp. 615-622
    • Patrick, G.N.1    Zukerberg, L.2    Nikolic, M.3    de la Monte, S.4    Dikkes, P.5    Tsai, L.H.6
  • 31
    • 33748752882 scopus 로고    scopus 로고
    • The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation
    • CrossRef Medline
    • Plattner F, Angelo M, Giese KP (2006) The roles of cyclin-dependent kinase 5 and glycogen synthase kinase 3 in tau hyperphosphorylation. J Biol Chem 281:25457-25465. CrossRef Medline
    • (2006) J Biol Chem , vol.281 , pp. 25457-25465
    • Plattner, F.1    Angelo, M.2    Giese, K.P.3
  • 33
    • 34250200796 scopus 로고    scopus 로고
    • P25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons
    • CrossRef Medline
    • Saito T, Konno T, Hosokawa T, Asada A, Ishiguro K, Hisanaga S (2007) P25/cyclin-dependent kinase 5 promotes the progression of cell death in nucleus of endoplasmic reticulum-stressed neurons. J Neurochem 102: 133-140. CrossRef Medline
    • (2007) J Neurochem , vol.102 , pp. 133-140
    • Saito, T.1    Konno, T.2    Hosokawa, T.3    Asada, A.4    Ishiguro, K.5    Hisanaga, S.6
  • 34
    • 0038206542 scopus 로고    scopus 로고
    • A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-Adeficient mice
    • Medline
    • Schmitt WB, Deacon RM, Seeburg PH, Rawlins JN, Bannerman DM (2003) A within-subjects, within-task demonstration of intact spatial reference memory and impaired spatial working memory in glutamate receptor-Adeficient mice. J Neurosci 23:3953-3959. Medline
    • (2003) J Neurosci , vol.23 , pp. 3953-3959
    • Schmitt, W.B.1    Deacon, R.M.2    Seeburg, P.H.3    Rawlins, J.N.4    Bannerman, D.M.5
  • 36
    • 0036193799 scopus 로고    scopus 로고
    • Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections
    • CrossRef Medline
    • Sun A, Nguyen XV, Bing G (2002) Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections. J Histochem Cytochem 50:463-472. CrossRef Medline
    • (2002) J Histochem Cytochem , vol.50 , pp. 463-472
    • Sun, A.1    Nguyen, X.V.2    Bing, G.3
  • 37
    • 84856007240 scopus 로고    scopus 로고
    • Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration
    • CrossRef Medline
    • Sundaram JR, Chan ES, Poore CP, Pareek TK, Cheong WF, Shui G, Tang N, Low CM, Wenk MR, Kesavapany S (2012) Cdk5/p25-induced cytosolic PLA2-mediated lysophosphatidylcholine production regulates neuroinflammation and triggers neurodegeneration. J Neurosci 32: 1020-1034. CrossRef Medline
    • (2012) J Neurosci , vol.32 , pp. 1020-1034
    • Sundaram, J.R.1    Chan, E.S.2    Poore, C.P.3    Pareek, T.K.4    Cheong, W.F.5    Shui, G.6    Tang, N.7    Low, C.M.8    Wenk, M.R.9    Kesavapany, S.10
  • 38
    • 0035933621 scopus 로고    scopus 로고
    • Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain
    • CrossRef Medline
    • Takashima A, Murayama M, Yasutake K, Takahashi H, Yokoyama M, Ishiguro K (2001) Involvement of cyclin dependent kinase5 activator p25 on tau phosphorylation in mouse brain. Neurosci Lett 306:37-40. CrossRef Medline
    • (2001) Neurosci Lett , vol.306 , pp. 37-40
    • Takashima, A.1    Murayama, M.2    Yasutake, K.3    Takahashi, H.4    Yokoyama, M.5    Ishiguro, K.6
  • 41
    • 0027978170 scopus 로고
    • P35 is a neuralspecific regulatory subunit of cyclin-dependent kinase 5
    • CrossRef Medline
    • Tsai LH, Delalle I, Caviness VS Jr, Chae T, Harlow E (1994) P35 is a neuralspecific regulatory subunit of cyclin-dependent kinase 5. Nature 371: 419-423. CrossRef Medline
    • (1994) Nature , vol.371 , pp. 419-423
    • Tsai, L.H.1    Delalle, I.2    Caviness Jr., V.S.3    Chae, T.4    Harlow, E.5
  • 42
    • 40449087334 scopus 로고    scopus 로고
    • Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 β mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing
    • CrossRef Medline
    • Wen Y, Planel E, Herman M, Figueroa HY, Wang L, Liu L, Lau LF, Yu WH, Duff KE (2008) Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 β mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing. J Neurosci 28:2624-2632. CrossRef Medline
    • (2008) J Neurosci , vol.28 , pp. 2624-2632
    • Wen, Y.1    Planel, E.2    Herman, M.3    Figueroa, H.Y.4    Wang, L.5    Liu, L.6    Lau, L.F.7    Yu, W.H.8    Duff, K.E.9
  • 43
    • 0035859053 scopus 로고    scopus 로고
    • P25 protein in neurodegeneration
    • discussion 764-765, CrossRef Medline
    • Yoo BC, Lubec G (2001) P25 protein in neurodegeneration. Nature 411: 763-764; discussion 764-765. CrossRef Medline
    • (2001) Nature , vol.411 , pp. 763-764
    • Yoo, B.C.1    Lubec, G.2
  • 44
    • 84866773764 scopus 로고    scopus 로고
    • Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer's disease
    • CrossRef Medline
    • Yu D, Corbett B, Yan Y, Zhang GX, Reinhart P, Cho SJ, Chin J (2012) Early cerebrovascular inflammation in a transgenic mouse model of Alzheimer's disease. Neurobiol Aging 33:2942-2947. CrossRef Medline
    • (2012) Neurobiol Aging , vol.33 , pp. 2942-2947
    • Yu, D.1    Corbett, B.2    Yan, Y.3    Zhang, G.X.4    Reinhart, P.5    Cho, S.J.6    Chin, J.7
  • 45
    • 0036379174 scopus 로고    scopus 로고
    • A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells
    • CrossRef Medline
    • Zheng YL, Li BS, Amin ND, Albers W, Pant HC (2002) A peptide derived from cyclin-dependent kinase activator (p35) specifically inhibits Cdk5 activity and phosphorylation of tau protein in transfected cells. Eur J Biochem 269:4427-4434. CrossRef Medline
    • (2002) Eur J Biochem , vol.269 , pp. 4427-4434
    • Zheng, Y.L.1    Li, B.S.2    Amin, N.D.3    Albers, W.4    Pant, H.C.5
  • 47
    • 77958594810 scopus 로고    scopus 로고
    • A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5-p25 hyperactivity and tau hyperphosphorylation
    • CrossRef Medline
    • Zheng YL, Amin ND, Hu YF, Rudrabhatla P, Shukla V, Kanungo J, Kesavapany S, Grant P, Albers W, Pant HC (2010) A 24-residue peptide (p5), derived from p35, the Cdk5 neuronal activator, specifically inhibits Cdk5-p25 hyperactivity and tau hyperphosphorylation. J Biol Chem 285: 34202-34212. CrossRef Medline
    • (2010) J Biol Chem , vol.285 , pp. 34202-34212
    • Zheng, Y.L.1    Amin, N.D.2    Hu, Y.F.3    Rudrabhatla, P.4    Shukla, V.5    Kanungo, J.6    Kesavapany, S.7    Grant, P.8    Albers, W.9    Pant, H.C.10
  • 48
    • 0032029111 scopus 로고    scopus 로고
    • Nitric oxide synthase inhibitors impair reference memory formation in a radial arm maze task in rats
    • CrossRef Medline
    • Zou LB, Yamada K, Tanaka T, Kameyama T, Nabeshima T (1998) Nitric oxide synthase inhibitors impair reference memory formation in a radial arm maze task in rats. Neuropharmacology 37:323-330. CrossRef Medline
    • (1998) Neuropharmacology , vol.37 , pp. 323-330
    • Zou, L.B.1    Yamada, K.2    Tanaka, T.3    Kameyama, T.4    Nabeshima, T.5


* 이 정보는 Elsevier사의 SCOPUS DB에서 KISTI가 분석하여 추출한 것입니다.