• Biomolecules & Therapeutics
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• v.29 no.3
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• pp.290-294
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• 2021

Extracellular beta amyloid (Aβ) plaques are the neuropathological hallmarks of Alzheimer's disease (AD). Accordingly, reducing Aβ levels is considered a promising strategy for AD prevention. 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside significantly decreased the Aβ production and this effect was accompanied with reduced sAPPβ production known as a soluble ectodomain APP fragment through β-secretases in HeLa cells overexpressing amyloid precursor proteins (APPs). This compound also increased the level of sAPPα, which is a proteolytic fragment of APP by α-secretases. In addition, 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside decreased the protein level of β-secretases, but the protein levels of A disintegrin and metalloproteinase (ADAM) family, especially ADAM10 and ADAM17, are increased. Thus, 3'-O-acetyl-24-epi-7,8-didehydrocimigenol-3-O-β-D-xylopryranoside could be useful in the development of AD treatment in the aspect of amyloid pathology.

• Biomolecules & Therapeutics
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• v.14 no.2
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• pp.106-109
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• 2006

Neprilysin (Nep) is known to be important to degrade $A{\beta}$ derived from amyloid precursor protein (APP) by cleavage with $\beta-and\;\gamma$-secretases. In order to determine whether a correspondence between $A{\beta}-42/{\gamma}-secretase$ activity and Nep levels exists in postnatal aging of transgenic mice expressing either neuron-specific enolase (NSE)-controlled human mutant presenilin-2 (hPS2m) or APPsw alone, the levels of Nep expression and $A{\beta}-42/{\gamma}-secretase$ activity were examined age of 5, 12, and 20 months, respectively. The levels of Nep expression in both types of transgenic brains were decreased relative to those of control mice in a aging-related manner, while the level of $A{\beta}-42/{\gamma}-secretase$ activity was reversibly increased. Thus, changes in $A{\beta}-42$ may all reflect variation in amounts of Nep enzyme.

• BMB Reports
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• v.52 no.4
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• pp.239-249
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• 2019

Membrane-anchored full-length MET stimulated by its ligand HGF/SF induces various biological responses, including survival, growth, and invasion. This panel of responses, referred to invasive growth, is required for embryogenesis and tissue regeneration in adults. On the contrary, MET deregulation is associated with tumorigenesis in many kinds of cancer. In addition to its well-documented ligand-stimulated downstream signaling, the receptor can be cleaved by proteases such as secretases, caspases, and calpains. These cleavages are involved either in MET receptor inactivation or, more interestingly, in generating active fragments that can modify cell fate. For instance, MET fragments can promote cell death or invasion. Given a large number of proteases capable of cleaving MET, this receptor appears as a prototype of proteolytic-cleavage-regulated receptor tyrosine kinase. In this review, we describe and discuss the mechanisms and consequences, both physiological and pathological, of MET proteolytic cleavages.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2006.04a
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• pp.109-120
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• 2006

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. The pathological hallmarks of AD are senile plaques and neurofibrillary tangles in the brain. Major component of senile plaques is amyloid beta peptide(A$\beta$) which is derived from amyloid precursor protein (APP). A$\beta$ is generated through the sequential cleavage of App by $\beta$ - and $\gamma$-secretases. $\beta$-secretase excises the ectodomain of APP ($\beta$-APPs) to leave a 99-amino acid long C-terminal fragment (APP-C99-CTF) in the membrane. $\gamma$-secretase then cleaves this membrane-tethered APP-CTF within the transmembrane domain, so releasing A$\beta$ peptides and APP-intracellular domain (AICD). Thus, $\beta$- and $\gamma$-secretase are regarded to perform the key steps in the pathogenesis of AD and have become important therapeutic targets in the prevention and treatment of AD. Enormous efforts have been focused to develop the amyloid beta related drug for cure of AD becuase A$\beta$ is believed to be one of the major causes of AD. since major pharmaceutical companies in world wide base compete to develop new drug for AD, we have to be careful to choose the drug target to success the tough race. In the present talk, possible drug targets based on basic research results will be discussed. These molecules should be a good target for development of new drug for AD and be less competitive to have a good shape for world wide competition.

• Biomolecules & Therapeutics
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• v.15 no.1
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• pp.34-39
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• 2007

Alzheimer's disease (AD) is an abnormal accumulation of the ${\beta}$-amyloid protein $(A{\beta})$ in specific brain region. It has been speculated that disturbance in cholesterol homeostasis may contribute to the etiology of AD by increasing $A{\beta}$ generation. However, conclusive evidence and possible mechanism has not been reported. In the present study, we demonstrated that rabbits treated with 0.5% cholesterol for 16 weeks increased serum total cholesterol, triacylglycerol, and low-density lipoprotein levels. $A{\beta}$ levels is higher in the hippocampus of brain in cholesterol dieted rabbits than that of normal diet rabbis. Expression and activities of ${\beta}-$ and ${\gamma}-$ secretases, the enzymes that cleave ${\beta}$-amyloid precursor protein to generate $A{\beta}$, were also increased in hippocampus of high cholesterol dieted rabbit than those of normal dieted rabbits. Our results suggest that high cholesterol diet may be associated with increased $A{\beta}$ accumulation in the brain of rabbits, and suggest that high cholesterol diet may be causal factor in the development or progression of AD.

• Journal of Acupuncture Research
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• v.23 no.2
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• pp.33-46
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• 2006

Alzheimer's disease (AD) is the most prevalent form of neurodegenerative disease associated with aging in the human population. This disease is characterized by the extracellular deposition of beta-amyloid peptide $(A{\beta})$ in cerebral plaques. $A{\beta}$ is derived from the ${\beta}-amyloid$ precursor protein (APP) by the enzymes, ${\beta}-$ and ${\eta}o-secretase$. Compounds that ${\beta}-$ or ${\eta}o-secretase$ inhibit activity, can reduce the production of $A{\beta}$ peptides, and thus have therapeutic potential in the treatment of AD. Increasing body of evidence has been demonstrated that Bee Venom(BV) Acupuncture could compete with complex protein involving in multiple step of $NF-{\kappa}B$ activation and exert the anti-inflammatory potential of combined inhibition of the prostanoid and nitric oxide synthesis systems by inhibition of IKK and $NF-{\kappa}B$. In this study, I investigated possible effects of BV on memory dysfunction caused by lipopolysaccharide (LPS) and $A{\beta}$ through inhibition of secretases activities and $A{\beta}$ aggregation. I examined the improving effect of BV on the LPS (2.5 mg/Kg, i.p.)-induced memory dysfunction using passive avoidance response and water maze tests in the mice. BV (0.84, $1.67\;{\mu}g/ml$) reversed the LPS-induced memorial dysfunction in dose dependent manner. BV also dose-dependently attenuated LPS-induced ${\beta}$ and ${\eta}o-secretase$ activities in cerebral cortex and hippocampus of the mice brain. This study therefore suggests that BV acupuncture method may be useful for prevention of development or progression of AD.