• Bulletin of the Korean Chemical Society
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• v.26 no.8
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• pp.1225-1228
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• 2005

C-terminal fragments of APP (APP-CTs), that contain A$\beta$ sequence, are found in neurotic plaques, neurofibrillary tangles and the cytosol of lymphoblastoid cells obtained from AD patients. CT26, Thr639-Asp664 (TVIVITLVMLKKKQYTSIHH GVVEVD) includes not only the transmembrane domain but also the cytoplasmic domain of APP. This sequence is produced from cleavage of APP by caspase and $\gamma$-secretase. In this study, the solution structure of CT26 was investigated using NMR spectroscopy and circular dichroism (CD) spectropolarimeter in various membrane-mimicking environments. According to CD spectra and the tertiary structure of CT26 determined in TFE-containing aqueous solution, CT26 has an α-helical structure from $Val^{2}\;to\;Lys^{11}$ in TFE-containing aqueous solution. However, according to CD data, CT26 adopts a $\beta$-sheet structure in the SDS micelles and DPC micelles. This result implies that CT26 may have a conformational transition between $\alpha$-helix and $\beta$-sheet structure. This study may provide an insight into the conformational basis of the pathological activity of the C-terminal fragments of APP in the model membrane.

• Food Science and Biotechnology
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• v.17 no.6
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• pp.1165-1170
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• 2008

The deposition of the amyloid $\beta}$ ($A{\beta}$)-peptide following proteolytic processing of amyloid precursor protein (APP) by $\beta$-secretase (BACE1) and $\gamma$-secretase is critical feature in the progress of Alzheimer's disease (AD). Consequently, BACE1, a key enzyme in the production of $A{\beta}$, is a prime target for therapeutic intervention in AD. In the course of searching for BACE1 inhibitors from natural sources, the ethyl acetate fraction of Petasites japonicus showed potent inhibitory activity. Two BACE1 inhibitors quercetin (QC) and kaempferol 3-O-(6"-acetyl)-$\beta$-glucopyranoside (KAG) were isolated from P. japonicus by activity-guided purification. QC, in particular, non-competitively attenuated BACE1 activity with $IC_{50}$ value of $2.1{\times}10^{-6}\;M$ and $K_i$ value of $3.7{\times}10^{-6}\;M$. Both compounds exhibited less inhibition of $\alpha$-secreatase (TACE) and other serine proteases including chymotrypsin, trypsin, and elastase, suggesting that they ere relatively specific and selective inhibitors to BACE1. Furthermore, both compounds significantly reduced the extracellular $A{\beta}$ secretion in $APP_{695}$-transfected B103 cells.

• Journal of Applied Biological Chemistry
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• v.64 no.2
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• pp.105-112
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• 2021

Excessive accumulation of the amyloid beta (Aβ) peptide has been implicated in the pathogenesis of Alzheimer's disease (AD). Paeonia lactiflora (PL) has been used in treatments of several conditions such as inflammation, arthritis, and cognitive impairment. The purpose of this study was to investigate the neuroprotective effect and mechanisms of PL and its active compound, paeoniflorin (PF), on Aβ_25-35-induced neurotoxicity in SH-SY5Y cells. We evaluated cell viability, lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) production. Furthermore, underlying mechanism of PL and PF on the regulation of amyloidogenic pathway was analyzed by Western blotting. In our results, Aβ_25-35-induced neuronal cell loss was observed, whereas treatment with PL (10, 50, and 100 ㎍/mL) and PF (1, 5, and 10 ㎍/mL) significantly elevated the cell viability, and decreased LDH release and ROS production. In addition, exposure of SH-SY5Y cells to Aβ_25-35 significantly increased the protein levels of amyloid precursor protein (APP)-C-terminal fragment β, β-site APP-cleaving enzyme, and presenilin-1 and -2. However, treatment with PL and PF inhibited the amyloidogenic pathway via the down-regulation of those protein expressions. Taken together, our results indicate that PL, and its active compound PF, could protect SH-SY5Y cells against Aβ_25-35-induced cell neurotoxicity by attenuating LDH release and ROS production, and these effects may be attributed to regulation of amyloidogenic pathway-related protein expression. In conclusion, PL and PF could be a potential to prevent neurodegenerative disorders such as AD.

• The Journal of Internal Korean Medicine
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• v.27 no.3
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• pp.603-616
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• 2006

The water extract of Gamiyaengshinhwan (GYH), has been used in vitro tests for its beneficial effects on neuronal survival and neuroprotective functions, particularly in connection with CT105-related dementias and Alzheimer's disease(AD). CT105 derived from proteolytic processing of the $\beta$-amyloid precursor protein (APP), including the amyloid-$\beta$ peptide ($A{\beta}$), plays a critical role in the pathogenesis of Alzheimer's dementia. We determined that transfected overexpressing APP695 and $A{\beta}$ CT105 have a profound attenuation in the Increase in CT105 expressing neuro2A cells from GYH. Experimental evidence indicates that GYH protects against neuronal damage from cells, but its cellular and molecular mechanisms remain unknown. Using a neuroblastoma cell line stably expressing CT105-associated neuronal degeneration, we demonstrated that GYH inhibits formation of amyloid-$\beta$ fragment ($A{\beta}$ CT105). which are the characteristic, and possibly causative, features of AD. The decreased CT105 $A{\beta}$ in the presence of GYH was observed in the conditioned medium of this CT105-secreting cell line under in vitro. In the cells, GYH significantly attenuated mitochondrion-initiated apoptosis and decreased the activity of Bax, a key enzyme in the apoptosis cell-signaling cascade. These results suggest that neuronal damage in AD might be due to two factors: a direct CT05 toxicity and the apoptosis initiated by the mitochondria. Multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of CT105 aggregation, underlie the neuroprotective effects of GYH.

• Journal of Physiology & Pathology in Korean Medicine
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• v.20 no.1
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• pp.43-51
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• 2006

This experiment was designed to investigate the effect of Amomum villosum(AMV) on the Alzheimer's disease. The effects of AMV extract on amyloid precursor proteins(APP), acetylcholinesterase(AChE), glial fibrillary acidic protein(GFAP) mRNA of PC-12 cell line treated by amyloid $\beta$ protein($A{\beta}$) : IL-$1{\beta}$, IL-6, TNF-$\alpha$ mRNA of THP-1 cell line treated by lipopolysaccharide(LPS) : AChE activity of PC-12 cell lysate treated by $A{\beta}$ : serum glucose, uric acid, AChE activity of memory deficit rats induced by scopolamine : behavior of memory deficit mice induced by scopolamine were investigated, respectively. AMV extract suppressed APP, AChE, GFAP mRNA in PC-12 cell treated by $A{\beta}$ : IL-$1{\beta}$, IL-6, TNF-$\alpha$ mRNA in THP-1 cell treated by LPS , AChE activity in cell lysate of PC-12 cell treated by $A{\beta}$. AMV extract increased glucose, decreased uric acid and AChE significantly in the serum of the memory deficit rats induced by scopolamine. AMV extract group showed significantly inhibitory effect on the memory deficit of mice induced by scopolamine in the experiment of Morris water maze. According to the above results, it is suggested that AMV extract might be usefully applied for prevention and treatment of Alzheimer's disease.

• Journal of Oriental Neuropsychiatry
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• v.17 no.2
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• pp.75-89
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• 2006

Objective : This experiment was designed to investigate the effect of Rhododendron simsii Planch(RSP) on the Alzheimer's disease. Method : The effects of RSP on amyloid precursor proteins(APP), acetylcholinesterase (AChE), glial fibrillary acidic protein(GFAP) mRNA of PC-12 cell treated by amyloid ${\beta}$ protein$(A{\beta})$ and $IL-1{\beta}$, IL-6, $TNF-{\alpha}$ mRNA of THP-1 cell treated by lipopolysaccharide(LPS), AChE activity of PC-12 cell lysate treated by $A{\beta}$ and behavior of the memory deficit mice induced by scopolamine, and glucose, AChE in serum of the memory deficit mice induced by scopolamine were investigated, respectively. Result : 1. RSP suppressed APP, AChE, GFAP mRNA in PC-12 celt treated by $A{\beta}$. 2. RSP suppressed $IL-1{\beta}$, IL-6, $TNF-{\alpha}$ mRNA in THP-1 cell treated by LPS. 3. RSP suppressed AChE activity in cell lysate of PC-12 cell treated by $A{\beta}$. 4. RSP increased glucose and decreased AChE significantly in the serum of the memory deficit mice induced by scopolamine. 5. RSP group showed significantly inhibitory effect on the scopolamine-induced impairment of teaming and. memory in the experiment of Morris water maze. Conclusion : According to the above results, it is suggested that RSP might be usefully applied for prevention and treatment of Alzheimer's disease and memory deficit symptom.

• Journal of Oriental Neuropsychiatry
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• v.15 no.2
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• pp.103-118
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• 2004

Objective : This experiment was designed to investigate the effect of KongJin-dan(KJD) on the Alzheimer's disease. Method : The effects of KJD on $LI-1{\beta}$, IL-6, $TNF-{\alpha}$, amyloid precursor proteins(APP), acetylcholinesterase(AChE), glial fibrillary acidic protein(GFAP) mRNA of PC-12 and THP-1 cell treated by CT105 and AChE activity, APP production of PC-12 cell lysate treated by CT105 were investigated, respectively. Results : 1. KJD suppressed $LI-1{\beta}$, IL-6, $TNF-{\alpha}$, APP, AChE, GFAP mRNA in THP-1 and PC-12 cell treated by CT105. 2. KJD suppressed AChE activity and production of APP significantly in cell lysate of PC-12 cell treated by CT105. Conclusions : This study shows that KJD might be usefully applied for prevention and treatment of Alzheimer's disease.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.271.2-271.2
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• 2003

The ${\gamma}$- and ${\beta}$-secretase are one of the most important proteases, which cleave amyloid precursor protein (APP) into neurotoxic A${\beta}$ peptide in Azheimer's type dementia. In the course of screening for anti-dementia agents from natural products, the mycelial culture of mushroom Phellinus linteus showed potent inhibition againt ${\beta}$-secretase (BACE1). (omitted)

• Journal of Oriental Neuropsychiatry
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• v.18 no.2
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• pp.101-132
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• 2007

Objective : This research investigates the effect of the NogYongDaeBoTang,(NYDBT) on Alzheimer's disease. Method : The effects of the NYDBT extract on (1) $IL-1{\beta}$, IL-6, and $TNF-{\alpha}$ mRNA of PC-12 cells treated with LPS; (2) acetylcholinesterase(AChE), amyloid precursor proteins(APP), and glial fibrillary acidic protein(GFAP) mRNA the AChE activity and the APP production of PC-12 cell treated with CT-105; (3) the behavior; (4) expression of $IL-1{\beta}$, $TNF-{\alpha}$, MDA, $IL-1{\beta}$ mRNA, and $TNF-{\alpha}$ mRNA; (5) the infarction area of the hippocampus, and brain tissue injury in Alzheimer‘s diseased mice induced with ${\beta}A$ were investigated. Results : 1. The NYDBT extract suppressed the expression of $IL-1{\beta}$, IL-6 and $TNF-{\alpha}$ mRNA in BV2 microglia cell line treated with LPS. 2. The NYDBT extract suppressed the expression of $IL-1{\beta}$, IL-6, and $TNF-{\alpha}$ protein production in BV2 microglia cell line treated with LPS. 3. For the NYDBT extract group a significant inhibitory effect on the memory deficit was shown for the mice with Alzheimer's disease induced by $A{\beta}$ in the Morris water maze experiment, which measured stop-through latency, and distance movement-through latency. 4. The NYDBT extract suppressed the over-expression of $IL-1{\beta}$ protein, $TNF-{\alpha}$ protein, MDA, and CD68/CD11b, in the mice with Alzheimer's disease induced by $A{\beta}$. 5. The NYDBT extract reduced the infarction area of hippocampus, and controlled the injury of brain tissue in the mice with Alzheimer's disease induced by $A{\beta}$. 6. The NYDBT extract reduced the Tau protein, GFAP protein, and presenilin1/2 protein (immunohistochemistry) of hippocampus in the mice with Alzheimer's disease induced by $A{\beta}$. Conclusions : These results suggest that the NYDBT extract may be effective for the prevention and treatment of Alzheimer's disease.

• Bulletin of the Korean Chemical Society
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• v.27 no.9
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• pp.1371-1376
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• 2006

BACE 1 ($\beta$-secretase), a membrane bound aspartic protease, is a key enzyme in the process of amyloid precursor protein (APP) into A$\beta$ peptide which is considered to play a causative role in Alzheimers Disease (AD). Here, we reported the synthesis and inhibitory activity of optically active 3-amino-4-aryl-piperidines.