• YAKHAK HOEJI
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• v.49 no.2
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• pp.147-150
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• 2005

Macrophage scavenger receptors (MSRs) induce microglial interaction with ${\beta}$-amyloid fibrils (fA${\beta}$) that are associated with Alzheimer's disease (AD). Although microglia are know n to have a dual effect on formation of plaque and clearance of fA${\beta}$ in the AD brain, receptor-mediated phagocytosis is a very important tool for preventing amyloid plaque via activated microglia in the early stage of AD. In the study, we examined whether ginsonoside Rg3 enhances the microglial Phagocytosis of A${\beta}$1-42 through Phagocytosis assay, gene expression (RT-PCR) and protein assay (western blots) for the cell responsiveness presented between Rg3-treated and non-treated groups. Fluro-labeled Ac-LDL and E.coli particles were used as control proteins for phagocytosis. In previous studies, this was a particularly interesting property of Rg3 in the stimulation and phagocytosis of macrophages in the periphery. We report here that ginsenoside Rg3 increased the expression of type-A MSR (MSR-A) in microglia and thus accelerated the phagocytosis with an effective degradation of engulfed fA${\beta}$. This result suggests that Rg3 may play an important role in removing fA${\beta}$ by enhancing the receptor-mediated phagocytosis. In addition, Rg3 could be a potential candidate for balancing the rate of production of fA${\beta}$ in AD brain.

• Molecules and Cells
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• v.40 no.1
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• pp.73-81
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• 2017

The ${\gamma}$-secretase complex represents an evolutionarily conserved family of transmembrane aspartyl proteases that cleave numerous type-I membrane proteins, including the ${\beta}$-amyloid precursor protein (APP) and the receptor Notch. All known rare mutations in APP and the ${\gamma}$-secretase catalytic component, presenilin, which lead to increased amyloid ${\beta}$-peptide production, are responsible for early-onset familial Alzheimer's disease. ${\beta}$-amyloid protein precursor-like (APPL) is the Drosophila ortholog of human APP. Here, we created Notch- and APPL-based Drosophila reporter systems for in vivo monitoring of ${\gamma}$-secretase activity. Ectopic expression of the Notch- and APPL-based chimeric reporters in wings results in vein truncation phenotypes. Reporter-mediated vein truncation phenotypes are enhanced by the Notch gain-of-function allele and suppressed by RNAi-mediated knockdown of presenilin. Furthermore, we find that apoptosis partly contributes to the vein truncation phenotypes of the APPL-based reporter, but not to the vein truncation phenotypes of the Notch-based reporter. Taken together, these results suggest that both in vivo reporter systems provide a powerful genetic tool to identify genes that modulate ${\gamma}$-secretase activity and/or APPL metabolism.

• YAKHAK HOEJI
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• v.49 no.2
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• pp.168-173
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• 2005

Alzheimers disease (AD) is the most prevalent form of neurodegenerations associated with aging in the human population. This disease is characterized by the extracellular deposition of beta-amyloid (A ${\beta}$) peptide in cerebral plaques. The A ${\beta}$ peptide is derived from the ${\beta}$-amyloid precursor protein ( ${\beta}$APP). Photolytic processing of ${\beta}$APP by ${\beta}$-secretase(beta-site APP-cleaving enzyme, BASE) and ${\gamma}$-secretase generates the A ${\beta}$ peptide. Several lines of evidence support that A ${\beta}$-induced neuronal cell death is major mechanisms of development of AD. Accordingly, the ${\beta}$-and ${\gamma}$-secretase have been implicated to be excellent targets for the treatment of AD. We previously found that sesaminol glucosides have improving effect on memory functions through anti-oxidative mechanism. In this study, to elucidate possible other mechanism (inhibition of ${\beta}$-and ${\gamma}$-secretase) of sesaminol glucosides, we examined the improving effect of sesaminol glucosides in the scopolamine (1 mg/kg/mouse)-induced memory dysfunction using water maze test in the mice. Sesaminol glucosides (3.75, 7.5 mg/kg/6ml/day p.o., for 3 weeks) reversed the latency time, distance and velocity by scopolamine in dose dependent manner. Next, ${\beta}$-and ${\gamma}$-secretase activities were determined in different regions of brain. Sesaminol glucosides dose-dependently attenuated scopolamine-induced ${\beta}$-secretase activities in cortex and hippocampous and ${\gamma}$-secretase in cortex. This study therefore suggests that sesaminol glucosides may be a useful agent for prevention of the development or progression of AD, and its inhibitory effect on secretase may play a role in the improving action of sesaminol glucosides on memory function.

• Journal of Oriental Neuropsychiatry
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• v.20 no.2
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• pp.121-131
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• 2009

Objectives : From Scrophularia buergeriana water extract(SBW), has been used in vivo test for its beneficial effects on neuronal survival and neuroprotective functions, particularly in connection with APP-related dementias and Alzheimer's disease(AD). $A{\beta}$ oligomer derived from proteolytic processing of the ${\beta}$-amyloid precursor protein(APP), including the amyloid-${\beta}$ peptide($A{\beta}$), play a critical role in the pathogenesis of Alzheimer's dementia. Methods : Using drosophila APP model on APP-induced neuronal cytotoxicity, we demonstrated that SBW prevents neurotoxicity of $A{\beta}$ oligomer, which are the behavior, and possibly causative, feature of AD. We investigated the neuroprotective effects of SBW against the effects of oligomeric $A{\beta}$ and fly behaveior and life span by UAS-GRIM/APP-GAL within transgenic flies. Results and Conclusions : SBW repaired damage leading to the behaveior of APP-induced fly and delayed life span. These results suggest that neuronal damage in AD might be due to two factors: a direct $A{\beta}$ oligomer toxicity and multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of $A{\beta}$ oligomer, underlie the neuroprotective effects of SBW.

• BMB Reports
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• v.43 no.10
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• pp.649-655
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• 2010

Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disorder and shows progressive memory loss and cognitive decline. Intraneuronal filaments composed of aggregated hyperphosphorylated tau protein, called neurofibrillary tangles, along with extracellular accumulations of amyloid $\beta$ protein (A$\beta$), called senile plaques, are known to be the neuropathological hallmarks of AD. In light of recent studies, epigenetic modification has emerged as one of the pathogenic mechanisms of AD. Epigenetic changes encompass an array of molecular modifications to both DNA and chromatin, including transcription factors and cofactors. In this review, we summarize how DNA methylation and changes to DNA chromatin packaging by post-translational histone modification are involved in AD. In addition, we describe the role of SIRTs, histone deacetylases, and the effect of SIRT-modulating drugs on AD. Lastly, we discuss how amyloid precursor protein (APP) intracellular domain (AICD) regulates neuronal transcription. Our understanding of the epigenomes and transcriptomes of AD may warrant future identification of novel biological markers and beneficial therapeutic targets for 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.

• 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.

• Journal of Life Science
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• v.29 no.2
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• pp.173-180
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• 2019

Amyloid ${\beta}$-protein ($A{\beta}$) is the principal component of senile plaques characteristic of Alzheimer's disease (AD) and elicits a toxic effect on neurons in vitro and in vivo. Many environmental factors, including antioxidants and proteoglycans, modify $A{\beta}$ toxicity. It is worthwhile to isolate novel natural compounds that could prove therapeutic for patients with AD without causing detrimental side effects. In this study, we investigated the in vitro neuroprotective effects of the ethyl acetate fraction of methanol extract of Ophiophogon japonicas (OJEA fraction). We used an MTT reduction assay to detect protective effects of the OJEA fraction on $A{\beta}_{25-35}$-induced cytotoxicity to PC12 cells. We also used a cell-based ${\beta}$-secretase assay system to investigate the inhibitory effect of the OJEA fraction on ${\beta}$-secretase activity. In addition, we performed an in vitro lipid peroxidation assay to evaluate the protective effect of the OJEA fraction against oxidative stress induced by $A{\beta}_{25-35}$ in PC12 cells. The OJEA fraction had strong protective effects against $A{\beta}_{25-35}$-induced cytotoxicity to PC12 cells and was strongly inhibitory to ${\beta}$-secretase activity, which resulted in the attenuation of $A{\beta}$ generation. In addition, the OJEA fraction significantly decreased malondialdehyde (MDA) content, which is induced by the exposure of PC12 cells to $A{\beta}_{25-35}$. Our results suggested that the OJEA fraction contained active compounds exhibiting a neuroprotective effect on $A{\beta}$ toxicity.

• Molecules and Cells
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• v.24 no.1
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• pp.113-118
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• 2007

The brains of Alzheimer's disease (AD) patients are characterized by large deposits of amyloid beta peptide ($A{\beta}$). $A{\beta}$ is known to increase free radical production in nerve cells, leading to cell death that is characterized by lipid peroxidation, free radical formation, protein oxidation, and DNA/RNA oxidation. In this study, we selected an extract of Gardenia jasminoides by screening, and investigated its ameliorating effects on $A{\beta}$-induced oxidative stress using PC12 cells. The effects of the extract were evaluated using the 2',7'-dichlorofluorescein diacetate (DCF-DA) assay and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction assay. To find the active component, the ethanol extract was partitioned with hexane, chloroform, and ethyl acetate, respectively, and the active component was purified by silica-gel column chromatography and HPLC. The results suggested that Gardenia jasminoides extract can reduce the cytotoxicity of $A{\beta}$ in PC 12 cells, possibly by reducing oxidative stress.