• BMB Reports
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• v.50 no.12
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• pp.634-639
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• 2017

We aimed to assess the anti-inflammatory and antioxidative properties of KHG26792, a novel azetidine derivative, in amyloid ${\beta}$ ($A{\beta}$)-treated primary microglial cells. KHG26792 attenuated the $A{\beta}-induced$ production of inflammatory mediators such as IL-6, $IL-1{\beta}$, $TNF-{\alpha}$, and nitric oxide. The levels of protein oxidation, lipid peroxidation, ROS, and NADHP oxidase enhanced by $A{\beta}$ were also downregulated by KHG26792 treatment. The effects of KHG26792 against the $A{\beta}-induced$ increases in inflammatory cytokine levels and oxidative stress were achieved by increasing the phosphorylation of $Akt/GSK-3{\beta}$ signaling and by decreasing the $A{\beta}-induced$ translocation of $NF-{\kappa}B$. Our results provide novel insights into the use of KHG26792 as a potential agent against $A{\beta}$ toxicity, including its role in the reduction of inflammation and oxidative stress. Nevertheless, further investigations of cellular signaling are required to clarify the in vivo effects of KHG26792 against $A{\beta}-induced$ toxicity.

• Molecules and Cells
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• v.27 no.6
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• pp.651-656
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• 2009

The formation of ${\beta}$-amyloid peptide ($A{\beta}$) is initiated from cleavage of amyloid precursor protein (APP) by a family of protease, ${\alpha}$-, ${\beta}$-, and ${\gamma}$-secretase. Sub W, a substrate peptide, consists of 10 amino acids, which are adjacent to the ${\beta}$-cleavage site of wild-type APP, and Sub M is Swedish mutant with double mutations on the left side of the ${\beta}$-cleavage site of APP. Sub W is a normal product of the metabolism of APP in the secretary pathway. Sub M is known to increase the efficiency of ${\beta}$-secretase activity, resulting in a more specific binding model compared to Sub W. Three-dimensional structures of Sub W and Sub M were studied by CD and NMR spectroscopy in water solution. On the basis of these structures, interaction models of ${\beta}$-secretase and substrate peptides were determined by molecular dynamics simulation. Four hydrogen bonds and one water-mediated interaction were formed in the docking models. In particular, the hydrogen bonding network of Sub M-BACE formed spread over the broad region of the active site of ${\beta}$-secretase (P5-P3'), and the side chain of P2- Asn formed a hydrogen bond specifically with the side chain of Arg235. These are more favorable to the cleavage of Sub M by ${\beta}$-secretase than Sub W. The two substrate peptides showed different tendency to bind to ${\beta}$-secretase and this information may useful for drug development to treat and prevent Alzheimer's disease.

• The Korean Journal of Food And Nutrition
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• v.30 no.6
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• pp.1279-1285
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• 2017

$Amyloid-{\beta}$ protein ($A{\beta}$) is known to increase free radical production in neuronal cells, leading to cell death by oxidative stress. The purpose of this study was to evaluate the protective effects of $PineXol^{(R)}$ on $A{\beta}_{25-35}$ induced neuronal cell death. Rat pheochromocytoma (PC-12) cells were pre-treated with $100{\mu}g/mL$ of $PineXol^{(R)}$ for 2 h. The cells were exposed to single dose of $30{\mu}M$ $A{\beta}_{25-35}$ for 24 h. Cell death was assessed by a cell count kit-8 (CCK-8) assay, lactate and dehydrogenase (LDH) release assay. An Apoptotic process was analyzed by a protein expression of the Bcl-2 family using western blotting. Cell viability increased in PC-12 cells treated with both $A{\beta}_{25-35}$ and $PineXol^{(R)}$, compared to the control group. $PineXol^{(R)}$ induced a decrease of the Bcl-2 protein expression (p<0.05), while Bax and Sod1 increased (p<0.05), indicating attenuation of $A{\beta}_{25-35}$ induced apoptosis. These results suggest that $PineXol^{(R)}$ may be a good candidate for the prevention of Alzheimer's disease(AD).

• Korean Journal of Biological Psychiatry
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• v.8 no.1
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• pp.62-70
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• 2001

Alzheimer's disease(AD) is associated with a characteristic neuropathology. The major hallmarks of AD are senile plaques (SPs) and neurofibrillary tangles(NFTs). ${\beta}$-amyloid protein($A{\beta}$) is derived from the proteolysis of amyloid precursor protein(APP) and then converted to SPs. Mature SPs produce cytotoxicity through direct toxic effects and activation of microglia and complement. NFTs are composed of paired helical filaments(PHFs) including abnormally phosphorylated form of the microtubule-associated protein(MAP) tau and increased tau level in cerebrospinal fluid may be observed in most AD. The aggregation of $A{\beta}$ and tau formation are thought to be a final common pathway of AD. Acetylcholine, dopamine, serotonin, GABA and their receptors are associated with AD. Especially, decreased nicotinic acetylcholine receptors(nAChRs) in AD are reported. Genetic lesions associated with AD are mutations in the structural genes for the APP located on chromosome 21, presenilin(PSN)1 located on chromosome 14 and PSN2 located on chromosome 1. Also, trisomy 21, Apo-E gene located on chromosome 19, PMF locus, low density lipoprotein receptor-related protein and ${\alpha}$-macroglobulin increase risk of AD. In this article, we will review about the neurobiology of AD and some newly developed research areas.

• Journal of Oriental Neuropsychiatry
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• v.12 no.2
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• pp.157-171
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• 2001

Astrocytes are glial cells that play a major role in the inflammation observed in Alzheimer's disease (AD). Upon stimulation from various agents, these cells adopt a reactive phenotype, a morphological hallmark in AD pathology, during which they themselves may produce still more inflammatory cytokines. Substance P (SP) can stimulate secretion of tumor necrosis $factor-\;{\alpha}$ $(TNF-\;{\alpha})$ from astrocytes stimulated with lipopolysaccharide (LPS). Here I report that Sunghyangjungkisan- ga- pogokyoung(Sgp) can modulate cytokines secretion from primary cultures of rat astrocytes. Sgp $(10\;to\;1000\;{\mu}g/ml)$ significantly inhibited the $TNF-\;{\alpha}$ secretion by astrocytes stimulated with LPS and SP. Interleukin-1 (IL-1) has been shown to elevate $TNF-\;{\alpha}$ secretion from LPS-stimulated astrocytes while having no effect on astrocytes in the absence of LPS. Treatment of Sgp $(10\;to\;1000\;{\mu}g/ml)$ to astrocytes stimulated with both LPS and SP decreased IL-1 secretion significantly. The secretion of $TNF-\;{\alpha}$ by LPS and SP in astrocytes was progressively inhibited with increasing amount of IL-1 neutralizing antibody. Neurodegenerative processes in AD are thought to be driven in part by the deposition of ${\beta}\;-amyloid\;(A\;{\beta})$, a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Sgp $(10\;to\;1000\;{\mu}g/ml)$ significantly inhibited the $TNF-\;{\alpha}$ secretion by astrocytes stimulated with $A-{\beta}-$and IL-1. These results suggest that Sgp may inhibit $TNF-\;{\alpha}$ secretion by inhibiting IL-1 secretion and that Sgp has an antiinflammatory activity in AD brain

• Journal of Oriental Neuropsychiatry
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• v.18 no.1
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• pp.63-78
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• 2007

Objective : This experiment was designed to investigate the effect of Thalictrum foetidum(TFD) on the Alzheimer's disease. Method : The effects of TFD 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-l 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. Results : The results were summarized as follows ; 1. TFD suppressed APP, AChE, GFAP mRNA in PC-12 cell treated by $A{\beta}$. 2. TFD suppressed $IL-1{\beta}$, IL-6, $TNF-{\alpha}$ mRNA in THP-l cell treated by LPS 3.. TFD suppressed AChE activity in cell lysate of PC-12 cell treated by $A{\beta}$. 4. TFD increased glucose and decreased AChE significantly in the serum of the memory deficit mice induced by scopolamine. 5. TFD group showed significantly inhibitory effect on the scopolamine-induced impairment of learning and memory in the experiment of Morris water maze. Conclusion : According to the above results, it is suggested that TFD might be usefully applied for prevention and treatment of Alzheimer's disease.

• The Journal of Korean Medicine
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• v.39 no.3
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• pp.1-16
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• 2018

Objectives: The purpose of this study was to investigate the effects of 56 herbal formulae covered by the National Health Insurance Corporation (NHIC) on dementia-related biomarkers and neuronal cell changes. Methods: The 56 herbal formulae were extracted with 70% ethanol at $100^{\circ}C$ for 2 h. The antioxidant properties was measured by radical scavenging assay using ABTS+ radical. The acetylcholinesterase (AChE) activity was tested by Ellman's assay and $amyloid-{\beta}$ ($A{\beta}$) aggregation was determined using fluorescence method. To estimate the inhibitory effects of herbal formulae on neuronal cell death and inflammation using HT22 hippocampal cells and BV-2 microglia, respectively. Results: Among the 56 herbal formulae, Dangguiyukhwangtang, Banhasasimtang, Samhwangsasimtang, Cheongwiesan, Hwangryunhaedoktang, Banhabaekchulchunmatang, Jaeumganghwatang, Cheongseoikgitang, and Hoechunyanggyuksan has a significant inhibitory effects on acetylcholinesterase (AChE) activity. Doinseunggitang and Samhwangsasimtang exerted the effect on the inhibition of $amyloid-{\beta}$ ($A{\beta}$) aggregation. Additionally, 10 herbal formulae affected AChE and $A{\beta}$ aggregation revealed antioxidant activity as well as neuroprotective and anti-neuroinflammation effects in neuronal cell lines. Conclusions: 10 herbal formulae that have been shown to be effective against the major dementia markers have been shown to have antioxidant activity, neuronal cell protection and inhibition of brain inflammation. Further investigation of these herbal formulae will need to be validated in dementia animal models.

• Journal of Physiology & Pathology in Korean Medicine
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• v.28 no.3
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• pp.317-321
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• 2014

Amyloid-${\beta}$ protein ($A{\beta}$) is a pathological component of Alzheimer's disease (AD) by participating in the senile plaque formation in the patient's brain. Although the exact mechanism of $A{\beta}$ toxicity is not fully elucidated, it is considered to be closely related to its fibrillation process. For prevention of AD, recent studies have suggested various small molecules which inhibit $A{\beta}$ fibrillation. In this report, ${\beta}$-asarone found in acorus plant has been investigated as an anti-amyloid molecule. ${\beta}$-Asarone was demonstrated to prevent in vitro fibrillation of $A{\beta}$ by inducing the oligomer formation that obviously decreased cytotoxicity. Therefore, ${\beta}$-asarone could be suggested as an inhibitory agent of $A{\beta}$ fibrillation and toxicity, which would help us not only to understand underlying principle of amyloidogenesis mechanism but also to develop a controlling strategy toward AD.

• Korean Journal of Biological Psychiatry
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• v.5 no.1
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• pp.66-70
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• 1998

Apoptosis is a form of cell death in which the cells shrink and exhibit nuclear chromatin condensation and DNA fragmentation, and yet maintain membrane integrity. Many lines of evidence have shown that brain neurons are vulnerable to degeneration by apoptosis. Also it has been suggested that apoptosis is one of the mechanism contributing neuronal loss in Alzheimer's disease(AD), since the conditions in the disease($A{\beta}$ peptide, oxidative stress, low energy metabolism) are the inducers that activate apoptosis. Indeed some neurons in vulnerable regions of the AD brain show DNA damage, chromatin condensation, and apoptic bodies. Consistently, mutations in AD causative genes(Amyloid precursor protein, Presenilin-1 and Presenilin- 2) increase $A{\beta}$ $peptide_{1-42}(A{\beta}_{1-42})$ and sensitize neuronal cell to apoposis. However, several lines of evidence have shown that the location of neuronal loss and $A{\beta}$ peptide deposition is not correlated in AD brain and transgenic mice brain over-expressing $A{\beta}_{1-42}$. Taken together, these data may indicated that $A{\beta}$ peptide(and other causative factors of AD) can interact with other cellular insults or risk factors to exacerbate pathological mechansim of AD through apoptosis. Thus, this review discusses possible role and mechanism of apoptosis in AD.

• Molecules and Cells
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• v.24 no.1
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• pp.69-75
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• 2007

Alzheimer's disease is a neurodegenerative disorder associated with progressive loss of cognitive function and memory. Amyloid beta peptide ($A{\beta}$) is the major component of senile plaques and is known to exert its cytotoxic effect mainly by producing $H_2O_2$. Vascular endothelial growth factor (VEGF) is elevated in the cerebrospinal fluid (CSF) and brain of AD patients, and $H_2O_2$ is one of the factors that induce VEGF. Therefore, we tested whether $A{\beta}$ might be responsible for the increased VEGF synthesis. We found that $A{\beta}$ induced the production of $H_2O_2$ in vitro. Comparison of the amount of $H_2O_2$ required to induce VEGF synthesis in HN33 cells and the amount of $H_2O_2$ produced by $10{\mu}M\;A{\beta}_{1-42}$ in vitro suggested that a toxic concentration of $A{\beta}$ might induce VEGF synthesis in these cells. However, toxic concentrations of $A{\beta}$ failed to induce VEGF synthesis in several cell systems. They also had no effect on antioxidant enzymes such as glutathione peroxidase, catalase, and peroxiredoxin in HN33 cells. $Cu^{2+}$, $Zn^{2+}$ and $Fe^{3+}$ are known to accumulate in the brains of AD patients and promote aggregation of $A{\beta}$, and $Cu^{2+}$ by itself induces synthesis of VEGF. However, there was no synergistic effect between $Cu^{2+}$ and $A{\beta}_{1-42}$ in the induction of VEGF synthesis and $Zn^{2+}$ and $Fe^{3+}$ also had no effect on the synthesis of VEGF, alone or in combination with $A{\beta}$.