▶ γ-secretase activity modulation during apoptosis

    Aβ is generated through the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. In spite of the importance of the γ-secretase as targets for AD therapy and the enormous progress in biochemical characterization of γ-secretase in recent years, there are only few reports elucidating the endogenous mechanism regulating γ-secretase activity. Some reports suggested that death signal regulate the processing of APP through modulation of secretase activity, but no details were provided. So, we are trying to elucidate the mechanism enhancing amyloidogenic processing of APP that was reported to happen during cell death using reporter system and in vitro peptide cleavage assay.

▶ Erk : intrinsic γ-secretase modulator

    Although much progress has been made in identifying the components of γ-secretase complex, which is believed to play an important role in the pathogenesis of Alzheimer’s disease, the endogenous regulatory mechanism of γ-secretase is currently unknown. We are trying to examine the possibility that MEK1/2-ERK1/2 kinase pathways are involved in the regulation of γ-secretase activity. The obtained results provided unequivocal evidence that ERK1/2 is an endogenous signaling agent that downregulates γ-secretase activity. Further studies on the relationship between ERK1/2 and the generation of Aβ should improve the understanding of the pathogenesis of AD.

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▶ Cholesterol and APP processing

    APP, Aβ and the γ-secretase complex molecules such as presenilin 1, nicastrin, Aph-1 and Pen-2 are all membrane proteins and membranes are composed of lipid bilayer including cholesterol rich lipid raft. We hypothesize that γ-secretase activity may be affected by changes in lipid metabolism such as cholesterol biosynthesis and lipid modification. In the present project, the relationship between lipid metabolism including cholesterol biosynthesis pathway and γ-secretase activation will be examined.

▶ Regulation of the BACE1 expression

    BACE1 is an essential protease to generate beta-amyloid peptide (Aβ), which is a significant pathological molecule of AD. Thus BACE1 has been supposed to be a nice target for AD treatment. Our recent findings show that BACE1 expression is regulated by AD-related pathological factors, such like inflammatory cytokines, Aβ, aging-related molecules. Studies on the mechanism of AD-induced BACE1 expression are on going.

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▶ Finding biomarkers for diagnosis of Alzheimer’s disease

    Alzheimer's disease (AD) is a neurodegenerative disorder that is rapidly increasing with the aging society. Thus, there is a pressing need for early diagnosis and prevention of AD. Diagnoses on AD, however, have only been possible through indirect methods. So, our current study is focused on finding biomarkers which might be able to directly distinguish AD patients from the normal people. To be precisely, by detecting abnormally altered expression of a certain protein in the blood from the disease suffering patient.

▶ Laboratory

    Our laboratory is located on the 9th floor of Samsung Cancer Research Building (cri.snu.ac.kr) in the Yeongeon medical campus of Seoul National University (medicine.snu.ac.kr). The official website of our laboratory is www.alzlab.co.kr, which is update regularly.

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▶ Peoples

Inhee Mook-Jung PhD
Associate Professor
Department of Biochemistry & Cancer Research Insitutute
Seoul National University College of Medicine
Seoul National University
Yeongeon-dong 28, Jongno-gu, Seoul, 110-799, Republic of Korea
(Lab) +82 2 3668 7974   //  (Office) +82 2 740 8245
+82 2 3672 7352 (Fax)
inhee@snu.ac.kr

Seok-Min Jin
Ph.D.
02-3668-7973
neurocom@snu.ac.kr

Hyun-Jin Cho
Ph.D. Candidate
02-3668-7973
zzini80c@snu.ac.kr

Jung-Hyun Boo
Graduate student, Ph.D. course
02-3668-7973
jhb00@snu.ac.kr

Ji-eun Kim

Graduate student, Ph.D. course

02-3668-7973

Sung-Min Sohn
Graduate student, MS course
02-3668-7973
sungmini119@naver.com

Mi-Yeon Shim
Graduate student, MS course
02-3668-7973
shimmy4@snu.ac.kr

Hyun-Ju Hong
Graduate student, MS course
02-3668-7973
hhj@snu.ac.kr

Eun-sun Jung

Graduate student, MS course 

02-3668-7973

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▶ Former people

Hyun-Seok Hong, Ph.D.
Post-Doctoral Fellow (Supervisor: Lee Way Jin)
M.I.N.D. Institute and Dept of Pathology
2805 50th Street
UC Davis Health System
Sacramento, CA 95817
Tel: 916-703-0392
Email: frogb104@hotmail.com

Eun-Mi Hwang, Ph.D.
Research Assistant Professor
Kyungsang Institute of Health sciences
Tel: 82- 055-751-8721
Email: emhwang@hanmail.net

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Song MS, Mook-Jung I, Lee HJ, Min JY, Park MH.
Serum anti-amyloid-beta antibodies and Alzheimer's disease in elderly Korean
patients. J Int Med Res. 2007 May-Jun;35(3):301-6. PMID: 17593857

Byeon SR, Lee JH, Sohn JH, Kim DC, Shin KJ, Yoo KH, Mook-Jung I, Lee WK, Kim
DJ. Bis-styrylpyridine and bis-styrylbenzene derivatives as inhibitors for Abetafibril formation.
Bioorg Med Chem Lett. 2007 Mar 1;17(5):1466-70. Epub 2006 Nov 2. PMID: 17270435

Cho HJ, Kim SK, Jin SM, Hwang EM, Kim YS, Huh K, Mook-Jung I.
IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2
signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes.Glia. 2007 Feb;55(3):253-62.PMID: 17091494

Hwang EM, Kim SK, Sohn JH, Lee JY, Kim Y, Kim YS, Mook-Jung I.
Furin is an endogenous regulator of alpha-secretase associated APP processing.
Biochem Biophys Res Commun. 2006 Oct 20;349(2):654-9. Epub 2006 Aug 22. PMID: 16942750

Jin SM, Cho HJ, Jung MW, Mook-Jung I.
DNA damage-inducing agent-elicited gamma-secretase activity is dependent on
Bax/Bcl-2 pathway but not on caspase cascades.
Cell Death Differ. 2007 Jan;14(1):189-92. Epub 2006 Jun 30. No abstract available. PMID: 16810324

Lee PH, Hwang EM, Hong HS, Boo JH, Mook-Jung I, Huh K.
Effect of ischemic neuronal insults on amyloid precursor protein processing.
Neurochem Res. 2006 Jun;31(6):821-7. Epub 2006 Jun 21.PMID: 16794858

Kang MJ, Chung YH, Hwang CI, Murata M, Fujimoto T, Mook-Jung IH, Cha CI, Park WY.
Caveolin-1 upregulation in senescent neurons alters amyloid precursor protein processing.
Exp Mol Med. 2006 Apr 30;38(2):126-33. PMID: 16672766

Lee EK, Park YW, Shin DY, Mook-Jung I, Yoo YJ.
Cytosolic amyloid-beta peptide 42 escaping from degradation induces cell death.
Biochem Biophys Res Commun. 2006 Jun 2;344(2):471-7. Epub 2006 Apr 4. PMID: 16630565

Lee J, Kang JH, Han KC, Kim Y, Kim SY, Youn HS, Mook-Jung I, Kim H, Lo Han JH, Ha HJ, Kim YH, Marquez VE, Lewin NE, Pearce LV, Lundberg DJ, Blumberg PM.
Branched diacylglycerol-lactones as potent protein kinase C ligands and alpha-secretase activators.
J Med Chem. 2006 Mar 23;49(6):2028-36. PMID: 16539391

Youm JW, Kim H, Han JH, Jang CH, Ha HJ, Mook-Jung I, Jeon JH, Choi CY, Kim YH, Kim HS, Joung H.
Transgenic potato expressing Abeta reduce Abeta burden in Alzheimer's disease mouse model.
FEBS Lett. 2005 Dec 19;579(30):6737-44. Epub 2005 Nov 21. PMID: 16310782

Kim SK, Park HJ, Hong HS, Baik EJ, Jung MW, Mook-Jung I. ERK1/2 is an endogenous negative regulator of the gamma-secretase activity. FASEB J. 2005 Nov 17; [Epub ahead of print] PMID: 16293708

Oh S, Hong HS, Hwang E, Sim HJ, Lee W, Shin SJ, Mook-Jung I.  Amyloid peptide attenuates the proteasome activity in neuronal cells. Mech Ageing Dev. 2005 Dec;126(12):1292-9. Epub 2005 Sep 8. PMID: 16153690

Youm JW, Kim H, Lo Han JH, Jang CH, Ha HJ, Mook-Jung I, Jeon JH, Choi CY, Kim YH, Kim HS, Joung H. Transgenic potato expressing Abeta reduce Abeta burden in Alzheimer's disease mouse model. FEBS Lett. 2005 Nov 21; [Epub ahead of print] PMID: 16310782

Lee PH, Bang OY, Hwang EM, Lee JS, Joo US, Mook-Jung I, Huh K. Circulating beta amyloid protein is elevated in patients with acute ischemic stroke. J Neural Transm. 2005 Oct;112(10):1371-9. Epub 2005 Jan 31. PMID: 15682267

Lee W, Kim DH, Boo JH, Kim YH, Park IS, Mook-Jung I. ER stress-induced caspase-12 activation is inhibited by PKC in neuronal cells. Apoptosis. 2005 Mar;10(2):407-15. PMID: 15843901

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