1. 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.
2. 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.
3. 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.
4. 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.
5. Finding biomarkers for diagnosis of Alzheimer’s diseaseAlzheimer'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 for Alzheimer's Disease Research,
#215 Biomedical Research Building, Seoul National University College of Medicine
28 Yeongeon-dong, Jongno-gu, Seoul 110-799, Korea. Tel) +82-2-3668-7636, Fax) +82-2-3672-7352