• Molecules and Cells
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• 제24권1호
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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 $A{\beta}$.

• The Korean Journal of Physiology and Pharmacology
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• 제13권3호
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• pp.195-200
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• 2009

Zinc released from excited glutamatergic neurons accelerates amyloid ${\beta}$ (A ${\beta}$) aggregation, underscoring the therapeutic potential of zinc chelation for the treatment of Alzheimer's disease (AD). Zinc can also alter A ${\beta}$ concentration by affecting its degradation. In order to elucidate the possible role of zinc influx in secretase-processed A ${\beta}$ production, SH-SY5Y cells stably expressing amyloid precursor protein (APP) were treated with pyrrolidine dithiocarbamate (PDTC), a zinc ionophore, and the resultant changes in APP processing were examined. PDTC decreased A ${\beta}$ 40 and A ${\beta}$ 42 concentrations in culture media bathing APP-expressing SH-SY5Y cells. Measuring the levels of a series of C-terminal APP fragments generated by enzymatic cutting at different APP-cleavage sites showed that both ${\beta}$-and ${\alpha}$-cleavage of APP were inhibited by zinc influx. PDTC also interfered with the maturation of APP. PDTC, however, paradoxically increased the intracellular levels of A ${\beta}$ 40. These results indicate that inhibition of secretase-mediated APP cleavage accounts -at least in part- for zinc inhibition of A ${\beta}$ secretion.

• 동의생리병리학회지
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• 제19권1호
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• pp.242-245
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• 2005

The most common feature of neurodegenerative disease (i.e. Alzheimer's disease, AD) is the increased number of activated microglial cells nearby the pathogenic area of the brain, such as amyloid plaque in AD. An abnormality of protein regulation and an imbalance of clearance against ${\beta}-amyloid\;(A{\beta})$ produced amyloid precursor protein (APP) can turn microglia into the activated feature out of the ramified resting phase. We examined the possibility that ginsenoside Rb1 could attenuate the microglial activation induced by massive $A{\beta}$ that has known to induce a chronic inflammation, which is a major cause of AD by damaging neuronal cells (i.e. apoptosis or necrosis). Aggregated $A{\beta}42\;(5\;{\mu}M)$ peptide was used with lipopolysaccharide (LPS) ($10\;{\mu}g$) for a comparative control up to 48hours. We found that Rb1 reduced the production of nitric oxide as well as proinflammatory cytokines, such as $IL-1{\beta}$ and $TNF-{\alpha}$.

• 한국약용작물학회:학술대회논문집
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• 한국약용작물학회 2006년도 Spring Conference
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• pp.75-90
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• 2006

Both synthetic and endogenous $A{\beta}$ are degraded by peptidase G. Both $A{\beta}40$ and 42 are cleaved by peptidase G. Peptidase G cleaves $A{\beta}40$ into small fragments ($A{\beta}18$) which lacks aggregation property and are not toxic to neuron. Peptidase G seems to degrade multimeric $A{\beta}$ more efficiently than monomeric $A{\beta}$. Peptidase G protects neurons from toxicity induced by $A{\beta}$ by cleaving it into smaller fragments. Thus, dis-regulation of peptidase G could contribute amyloid deposit found in AD brain.

• 대한한의학회지
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• 제35권4호
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• pp.10-23
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• 2014

Objectives: This study evaluated the effects of Guibi-tang (GBT) on neuronal apoptosis and cognitive impairment induced by beta amyloid ($A{\beta}$), (1-42) injection in the hippocampus of ICR mice. Methods: $A{\beta}$ (1-42) was injected unilaterally into the lateral ventricle using a Hamilton syringe and micropump ($2{\mu}g/3{\mu}{\ell}$, $0.6{\mu}{\ell}/min$). Water extract of GBT was administered orally once a day (500 mg/kg) for 3 weeks after the $A{\beta}$ (1-42) injection. Acquisition of learning and retention of memory were tested using the Morris water maze. Neuronal damage and $A{\beta}$ accumulation in the hippocampus was observed using cresyl violet and Congo red staining. The anti-apoptotic effect of GBT was evaluated using TUNEL labeling in the hippocampus. Results: GBT significantly shortened the escape latencies during acquisition training trials. GBT significantly increased the number of target headings to the platform site, the swimming time spent in the target quadrant, and significantly shortened the time for the 1st target heading during the retention test trial. GBT significantly attenuated the reduction in thickness and number of CA1 neurons, and $A{\beta}$ accumulation in the hippocampus produced by $A{\beta}$ (1-42) injection. GBT significantly reduced the number of TUNEL-labeled neurons in the hippocampus. Conclusion: These results suggest that GBT improved cognitive impairment by reducing neuronal apoptosis and $A{\beta}$ accumulation in the hippocampus. GBT may be a beneficial herbal formulation in treating cognitive impairment including Alzheimer's disease.

• The Korean Journal of Physiology and Pharmacology
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• 제11권5호
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• pp.163-169
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• 2007

The neurotoxicity of amyloid $\beta(A\beta)$ is associated with an increased production of reactive oxygen species and apoptosis, and it has been implicated in the development of Alzheimer's disease. While(-)-epigallocatechin-3-gallate(EGCG) suppresses $A\beta$-induced apoptosis, the mechanisms underlying this process have yet to be completely clarified. This study was designed to investigate whether EGCG plays a neuroprotective role by activating cell survival system such as protein kinase C(PKC), extracellular-signal-related kinase(ERK), c-Jun N-terminal kinase(JNK), and anti-apoptotic and pro-apoptotic genes in SH-SY5Y human neuroblastoma cells. One ${\mu}M\;A{\beta}_{1-42}$ decreased cell viability, which was correlated with increased DNA fragmentation evidenced by DAPI staining. Pre-treatment of SH-SY5Y neuroblastoma cells with EGCG($1{\mu}M$) significantly attenuated $A{\beta}_{1-42}$-induced cytotoxicity. Potential cell signaling candidates involved in this neuroprotective effects were further examined. EGCG restored the reduced PKC, ERK, and JNK activities caused by $A{\beta}_{1-42}$ toxicity. In addition, gene expression analysis revealed that EGCG prevented both the $A{\beta}_{1-42}$-induced expression of a pro-apoptotic gene mRNA, Bad and Bax, and the decrease of an anti-apoptotic gene mRNA, Bcl-2 and Bcl-xl. These results suggest that the neuroprotective mechanism of EGCG against $A{\beta}_{1-42}$-induced apoptotic cell death includes stimulation of PKC, ERK, and JNK, and modulation of cell survival and death genes.

• Biomolecules & Therapeutics
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• 제19권3호
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• pp.288-295
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• 2011

Amyloid beta ($A{\beta}$)-induced neurotoxicity is a major pathological mechanism of Alzheimer's disease (AD). In this study, we investigated the inhibitory effect of L-theanine, a component of green tea (Camellia sinensis) on $A{\beta}_{1-42}$-induced neurotoxicity and oxidative damages of macromolecules. L-theanine inhibited $A{\beta}_{1-42}$-induced generation of reactive oxygen species, and activation of extracellular signal-regulated kinase and p38 mitogenic activated protein kinase as well as the activity of nuclear factor kappa-B. L-theanine also signifi cantly reduced oxidative protein and lipid damage, and elevated glutathione level. Consistent with the reduced neurotoxic signals, L-theanine (10-50 ${\mu}g$/ml) concomitantly attenuated $A{\beta}_{1-42}$ (5 ${\mu}M$)-induced neurotoxicity in SK-N-MC and SK-N-SH human neuroblastoma cells. These data indicate that L-theanine on $A{\beta}$-induced neurotoxicity prevented oxidative damages of neuronal cells, and may be useful in the prevention and treatment of neurodegenerative disease like AD.

• 한국응용약물학회:학술대회논문집
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• 한국응용약물학회 2006년도 Spring Conference
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• pp.77-90
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• 2006

Beta-amyloid peptide (A$\beta$) is a major component of senile plaques and its aggregation is considered to play a critical role in pathogenesis of Alzheimer's disease (AD). Aggregation of A$\beta$ could result from both increased synthesis and decreased degradation of A$\beta$. Our laboratory is interested in understanding the mechanism of A$\beta$ degradation in brain. Recently our laboratory identified a bacterial gene (SKAP) from Streptomyces sp KK565 whose protein product has an activity to cleave A$\beta$ and thus reduce the A$\beta$-induced neurotoxicity. The sequence analysis showed that this gene was closely related to aminopeptidase. Maldi-Tof analysis showed that the recombinant SKAP protein expressed in E. coli cleaves both A$\beta$ 40 and A$\beta$ 42 at the N-terminal of A$\beta$ while an aminopeptidase from Streptomyces griseus (SGAP) cleaves at the C-terminal. We also identified a mammalian homolog of SKAP and the recombinant mammalian protein expressed in Sf-9 insect cells showed a similar proteolytic activity to SGAP, cutting A$\beta$ at the C-terminus. I well discuss the detailed mechanism of the enzyme action and its functional implication in AD.

• Bulletin of the Korean Chemical Society
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• 제33권11호
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• pp.3671-3675
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• 2012

${\beta}$-Amyloid accumulation in the brain is a pathological hallmark of Alzheimer's disease (AD). Since early detection of ${\beta}$-amyloid may facilitate more successful and timely therapeutic interventions, many investigators have focused on developing AD diagnostic reagents that can penetrate the blood-brain barrier (BBB). Oleanolic acid (OA) is a substance found in a variety of plants that has been reported to prevent the progression of AD in mice. In this study, we synthesized and evaluated a new radioligand in which OA was conjugated to lactoferrin (Lf, an iron-binding glycoprotein that crosses the BBB) for the diagnosis of AD. In an in vitro study in which OA-Lf was incubated with ${\beta}$-amyloid (1-42) aggregates for 24 h, we found that OA-Lf effectively inhibited ${\beta}$-amyloid aggregation and fibril formation. In vivo studies demonstrated that $^{123}I$-OA-Lf brain uptake was higher than$^{123}I$-Lf uptake. Therefore, radiolabeled OA-Lf may have diagnostic potential for ${\beta}$-amyloid imaging.

• 생약학회지
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• 제46권1호
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• pp.72-77
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• 2015

One of the most common forms of dementia, Alzheimer's disease (AD) is a progressive neurodegenerative disorder symptomatically characterized by impairment in memory and cognitive abilities. AD is characterized pathologically by the presence of intracellular neurofibrillary tangles and deposition of ${\beta}$-amyloid ($A{\beta}$) peptides, believed to be neurotoxic and now is also considered to have a role on the mechanism of memory dysfunction. In this study, we tested that MeOH extract of Impatiens balsamina L. (IBM) affects on the processing of APP from the APPswe over-expressing Neuro2a cell line. We found that IBM increased over 2 folds of the $sAPP{\alpha}$ secretion level, a main metabolite of ${\alpha}$-secretase. We shown that IBM reduced the secretion level of $A{\beta}42$ and $A{\beta}40$ without cytotoxicity. BACE (${\beta}$-site APP cleaving enzyme) FRET assay shown that BACE activity was specifically decreased in the presence of IBM. We suggest that Impatiens balsamina L. may be an useful source to develop a herbal medicine of BACE inhibitor for Alzheimer's disease.