• The Korean Journal of Physiology and Pharmacology
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• v.22 no.6
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• pp.689-696
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• 2018

Increasing evidence implicates changes in $[Ca^{2+}]_i$ and oxidative stress as causative factors in amyloid beta ($A{\beta}$)-induced neuronal cell death. Cyanidin-3-glucoside (C3G), a component of anthocyanin, has been reported to protect against glutamate-induced neuronal cell death by inhibiting $Ca^{2+}$ and $Zn^{2+}$ signaling. The present study aimed to determine whether C3G exerts a protective effect against $A{\beta}_{25-35}$-induced neuronal cell death in cultured rat hippocampal neurons from embryonic day 17 fetal Sprague-Dawley rats using MTT assay for cell survival, and caspase-3 assay and digital imaging methods for $Ca^{2+}$, $Zn^{2+}$, MMP and ROS. Treatment with $A{\beta}_{25-35}$ ($20{\mu}M$) for 48 h induced neuronal cell death in cultured rat pure hippocampal neurons. Treatment with C3G for 48 h significantly increased cell survival. Pretreatment with C3G for 30 min significantly inhibited $A{\beta}_{25-35}$-induced $[Zn^{2+}]_i$ increases as well as $[Ca^{2+}]_i$ increases in the cultured rat hippocampal neurons. C3G also significantly inhibited $A{\beta}_{25-35}$-induced mitochondrial depolarization. C3G also blocked the $A{\beta}_{25-35}$-induced formation of ROS. In addition, C3G significantly inhibited the $A{\beta}_{25-35}$-induced activation of caspase-3. These results suggest that cyanidin-3-glucoside protects against amyloid ${\beta}$-induced neuronal cell death by reducing multiple apoptotic signals.

• Journal of Microbiology and Biotechnology
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• v.13 no.5
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• pp.809-814
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• 2003

${\beta}-amyloid$ ($A{\beta}$) peptides from the proteolytic processing of ${\beta}-amyloid$ precursor protein (${\beta}-APP$) aggregates in the brain to form senile plaques, and their aggregation plays a key role in pathogenesis of Alzheimer's disease (AD). To isolate an active compound that has an $A{\beta}$ aggregation-inhibitory activity, 2,000 microbial metabolite libraries were screened based on their ability to inhibit $A{\beta}$ aggregation by using both Congo red and thioflavin T assays. As a result, a water-soluble fraction of a soil microorganism, KK565, showed a potent $A{\beta}$ aggregation-inhibitory activity. The strain was identified as Streptomyces species, based on the cultural and morphological characteristics, the presence of diaminopimelic acid in the cell wall, and the sugar patterns for the whole-cell extract. In addition, the purification of active principle resulted in identifying a heat-unstable protein responsible for the $A{\beta}$ aggregation-inhibitory activity.

• Journal of Ginseng Research
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• v.37 no.1
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• pp.100-107
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• 2013

This study examined the effect of fermented ginseng (FG) on memory impairment and ${\beta}$-amyloid ($A{\beta}$) reduction in models of Alzheimer's disease (AD) in vitro and in vivo. FG extract was prepared by steaming and fermenting ginseng. In vitro assessment measured soluble $A{\beta}42$ levels in HeLa cells, which stably express the Swedish mutant form of amyloid precursor protein. After 8 h incubation with the FG extract, the level of soluble $A{\beta}42$ was reduced. For behavioral assessments, the passive avoidance test was used for the scopolamine-injected ICR mouse model, and the Morris water maze was used for a transgenic (TG) mouse model, which exhibits impaired memory function and increased $A{\beta}42$ level in the brain. FG extract was treated for 2 wk or 4 mo on ICR and TG mice, respectively. FG extract treatment resulted in a significant recovery of memory function in both animal models. Brain soluble $A{\beta}42$ levels measured from the cerebral cortex of TG mice were significantly reduced by the FG extract treatment. These findings suggest that FG extract can protect the brain from increased levels of $A{\beta}42$ protein, which results in enhanced behavioral memory function, thus, suggesting that FG extract may be an effective preventive or treatment for AD.

• Journal of Acupuncture Research
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• v.20 no.4
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• pp.145-156
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• 2003

Objective : This study is to investigate the effect of electro-acupuncture ST36 on altered transmission of afferent somatosensory information caused by amyloid-${\beta}$(A-${\beta}$) that caused Alzheimer's disease. Methods : The effects of topical application of A-${\beta}$, A-${\beta}$ with ST36, aggregated A-${\beta}$(aA-${\beta}$), aA-${\beta}$ with ST36 and ST36 on the afferent sensory transmission to the neurons in the primary somatosensory(SI) cortex was observed in anesthetized rats. Quantitative determination of the effects of A-${\beta}$, A-${\beta}$ with ST36, aA-${\beta}$, aA-${\beta}$ with ST36 and ST36 was made by generating poststimulus time histogram of evoked response of individual cortical neuron by electrical stimulation of the receptive located in peripheral area(forepaw) Results : The results obtained in present study were summerized as follow : 1. Application of physiological concentrative 0.5 nM A-${\beta}$ caused afferent sensory transmission of SI cortex facilitated. 0.5 nM A-${\beta}$ with ST36 exerted much stronger effects than 0.5 nM A-${\beta}$ alone. 2. Application of $10{\mu}M$ A-${\beta}$ caused afferent sensory transmission of SI cortex unchangeable. But $10{\mu}M$ A-${\beta}$ with ST36 is facilitated at 30 min of post-drug period 3. Application of $10{\mu}M$ aA-${\beta}$ caused afferent sensory transmission of SI cortex diminished. $10{\mu}M$ aA-${\beta}$ with ST36 is diminished after 15min of post-drug period but is facilitated after 75min.

• Preventive Nutrition and Food Science
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• v.16 no.1
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• pp.18-23
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• 2011

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by neuronal loss and extracellular senile plaques containing $\beta$-amyloid peptide (A$\beta$). The deposition of the A$\beta$ peptide following proteolytic processing of amyloid precursor protein (APP) by $\beta$-secretase (BACE1) and $\gamma$-secretase is a critical feature in the progression of AD. Among the plant extracts tested, the ethanol extract of Petasites japonicus leaves showed novel protective effect on B103 neuroblastoma cells against neurotoxicity induced by A$\beta$, as well as a strong suppressive effect on BACE1 activity. Ethanol extracts of P. japonicus leaves were sequentially extracted with methylene chloride, ethyl acetate and butanol and evaluated for potential to inhibit BACE1, as well as to suppress A$\beta$-induced neurotoxicity. Exposure to A$\beta$ significantly reduced cell viability and increased apoptotic cell death. However, pretreatment with ethyl acetate fraction of P. japonicus leaves prior to A$\beta$ (50 ${\mu}M$) significantly increased cell viability (p<0.01). In parallel, cell apoptosis triggered by A$\beta$ was also dramatically inhibited by ethyl acetate fraction of P. japonicus leaves. Moreover, the ethyl acetate fraction suppressed caspase-3 activity to the basal level at 30 ppm. Taken together, these results demonstrated that P. japonicus leaves appear to be a useful source for the inhibition and/or prevention of AD by suppression of BACE1 activity and attenuation of A$\beta$ induced neurocytotoxicity.

• YAKHAK HOEJI
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• v.54 no.6
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• pp.529-534
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• 2010

Alzheimer's disease (AD) is characterized pathologically by the presence of intracellular neurofibrillary tangles and deposition of ${\beta}$-amyloid ($A{\beta}$) peptides, which are generated by processing of amyloid precursor protein (APP). It is urgent to develop effective therapies for the treatment of AD, since our society rapidly accelerate aging. $A{\beta}$ peptides have been believed to be neurotoxic and now are also considered to have effects on the mechanism of memory formation. Recently, we investigated that a quinoline compound from natural product reduced the secretion of $A{\beta}$ from the neuroblastoma N2a cells (NL/N cell line) overexpressing APPswe. In this study, 3-phenyl-1-isoquinolinamine, a synthetic isoquinoline compound was analyzed to determine its effects on the metabolism of APP. It inhibited the secretion of $A{\beta}$ peptides from the N2a NL/N cell line. Beta-site APP cleaving enzyme (BACE) fluorescence resonance energy transfer (FRET) assay revealed that it inhibited BACE activity in a dose dependent manner. Immunoblotting study showed that it inhibited APP stabilization and expression and it slightly increased the stablization and the expression of ${\gamma}$-secreatase component from the N2a NL/N cell line. We suggest that 3-phenyl-1-isoquinolinamine inhibits APP metabolism and $A{\beta}$ generation by the means of BACE inhibitory mechanism. This is the first report that 3-phenyl-1-isoquinolinamine inhibits the secretion of $A{\beta}$ peptides from neuroblastoma cells.

• Korean Journal of Pharmacognosy
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• v.49 no.2
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• pp.182-187
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• 2018

Many plant derived phytochemicals have been considered as the main therapeutic strategy against Alzheimer's disease (AD). AD is a progressive neurodegenerative disorder, and the most predominant cause of dementia in the elderly. Cholinergic deficit, senile plaque/${\beta}$-amyloid ($A{\beta}$) peptide deposition and oxidative stress have been identified as three main pathogenic pathways which contribute to the progression of AD. We screened many different plant species for their effective use in both modern and traditional system of medicines. In this study, we tested that MeOH extract of the stem bark of Hopea chinensis (Merr.) Hand.-Mazz. (HCM) affects on the processing of Amyloid precursor portein (APP) from the APPswe over-expressing Neuro2a cell line. We showed that HCM reduced the secretion level of $A{\beta}42$ and $A{\beta}40$ in a dose dependent manner. We found that HCM increased over 1.5 folds of the secretion level of $sAPP{\alpha}$, a metabolite of ${\alpha}$-secretase. Furthermore, we found that HCM inhibited acetylcholinesterase activity in vitro. We suggest that the stem bark of Hopea chinensis may be a useful source to develop a therapeutics for AD.

• Korean Journal of Medicinal Crop Science
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• v.22 no.2
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• pp.105-112
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• 2014

The present study investigated an ethanol extract (SSB) of a mixture of three medicinal plants of Vitis amurensis, Aralia cordata, and Glycyrrhizae radix for possible neuroprotective effects on neurotoxicity induced by Amyloid ${\beta}$ protein ($A{\beta}$) (25-35) in cultured rat cortical neurons and antidementia activity in mice. Exposure of cultured cortical neurons to $15{\mu}M$ $A{\beta}$ (25-35) for 36 h induced neuronal apoptotic death. At $1-30{\mu}g/m{\ell}$, SSB inhibited neuronal death, elevation of intracellular calcium concentration ($[Ca^{2+}]_i$), and generation of reactive oxygen species (ROS) induced by $A{\beta}$ (25-35) in cultured cortical neurons. Memory impairment and increase of acetylcholinesterase activity induced by intracerebroventricular injection of mice with 16 nmol $A{\beta}$ (25-35) was inhibited by chronic treatment with SSB (25, 50 and 100 mg/kg, p.o., for 8 days). From these results, it is suggested that antidementia effect of SSB is due to its neuroprotective effect against $A{\beta}$ (25-35)-induced neurotoxicity and that SSB may have a therapeutic role in preventing the progression of Alzheimer's disease.

• Proceeding of EDISON Challenge
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• 2014.03a
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• pp.237-249
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• 2014

Deposition of amyloid-${\beta}$ ($A{\beta}$) proteins is the conventional pathological hallmark of Alzheimer's disease (AD). The $A{\beta}$ protein formed from the amyloid precursor protein is predominated by the 40 residue protein ($A{\beta}40$) and by the 42 residue protein ($A{\beta}42$). While $A{\beta}40$ and $A{\beta}42$ differ in only two amino acid residues at the C-terminal end, $A{\beta}42$ is much more prone to aggregate and exhibits more neurotoxicity than $A{\beta}40$. Here, we investigate the molecular origin of the difference in the aggregation propensity of these two proteins by performing fully atomistic, explicit-water molecular dynamics simulations. Then, it is followed by the solvation thermodynamic analysis based on the integral-equation theory of liquids. We find that $A{\beta}42$ displays higher tendency to adopt ${\beta}$-sheet conformations than $A{\beta}40$, which would consequently facilitate the conversion to the ${\beta}$-sheet rich fibril structure. Furthermore, the solvation thermodynamic analysis on the simulated protein conformations indicates that $A{\beta}42$ is more hydrophobic than $A{\beta}40$, implying that the surrounding water imparts a larger thermodynamic driving force for the self-assembly of $A{\beta}42$. Taken together, our results provide structural and thermodynamic grounds on why $A{\beta}42$ is more aggregation-prone than $A{\beta}40$ in aqueous environments.

• Proceeding of EDISON Challenge
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• 2015.03a
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• pp.14-23
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• 2015

Alzheimer's disease is one of the most common types of degenerative dementia. As a considerable cause of Alzheimer's disease, neurotoxic plaques composed of 39 to 42 residue-long amyloid beta($A{\beta}$) fibrils have been found in the patient's brain in large quantity. A previous study found that erythrosine B (ER), a red color food dye approved by FDA, inhibits the formation of amyloid beta fibril structures. Here, in an attempt to elucidate the inhibition mechanism, we performed molecular dynamics simulations to demonstrate the conformational change of $A{\beta}40$ induced by 2 ERs in atomistic detail. During the simulation, the ERs bound to the surfaces of both N-terminus and C-terminus regions of $A{\beta}40$ rapidly. The observed stacking of the ERs and the aromatic side chains near the N-terminus region suggests a possible inhibition mechanism in which disturbing the inter-chain stacking of PHEs destabilizes beta-sheet enriched in amyloid beta fibrils. The bound ERs block water molecules and thereby help stabilizing alpha helical structure at the main chain of C-terminus and interrupt the formation of the salt-bridge ASP23-LYS28 at the same time. Our findings can help better understanding of the current and upcoming treatment studies for Alzheimer's disease by suggesting inhibition mechanism of ER on the conformational transition of $A{\beta}40$ at the molecular level.