• 약학회지
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• 제49권2호
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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.

• Biomolecules & Therapeutics
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• 제23권2호
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• pp.156-164
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• 2015

Alzheimer's disease (AD) is a neurodegenerative disorder associated with progressive memory loss and neuronal cell death. Although numerous previous studies have been focused on disease progression or reverse pathological symptoms, therapeutic strategies for AD are limited. Alternatively, the identification of traditional herbal medicines or their active compounds has received much attention. The aims of the present study were to characterize the ameliorating effects of spinosin, a C-glucosylflavone isolated from Zizyphus jujuba var. spinosa, on memory impairment or the pathological changes induced through amyloid-${\beta}_{1-42}$ oligomer ($A{\beta}O$) in mice. Memory impairment was induced by intracerebroventricular injection of $A{\beta}O$ ($50{\mu}M$) and spinosin (5, 10, and 20 mg/kg) was administered for 7 days. In the behavioral tasks, the subchronic administration of spinosin (20 mg/kg, p.o.) significantly ameliorated $A{\beta}O$-induced cognitive impairment in the passive avoidance task or the Y-maze task. To identify the effects of spinosin on the pathological changes induced through $A{\beta}O$, immunohistochemistry and Western blot analyses were performed. Spinosin treatment also reduced the number of activated microglia and astrocytes observed after $A{\beta}O$ injection. In addition, spinosin rescued the $A{\beta}O$-induced decrease in choline acetyltransferase expression levels. These results suggest that spinosin ameliorated memory impairment induced through $A{\beta}O$, and these effects were regulated, in part, through neuroprotective activity via the anti-inflammatory effects of spinosin. Therefore, spinosin might be a useful agent against the amyloid ${\beta}$ protein-induced cognitive dysfunction observed in AD patients.

• 한국산학기술학회논문지
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• 제20권2호
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• pp.286-293
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• 2019

알츠하이머 질환은 대표적인 신경퇴행성 질환으로, 뇌 내에서 $A{\beta}$ 단백질 축적은 알츠하이머 질환의 원인으로 알려져 있다. 본 연구에서는 amyloid beta ($A{\beta}$)로 손상을 유도한 SH-SY5Y 신경세포에서 kaempferol, kaempferol-3-O-glucoside, quercetin, quercetin-3-${\beta}$-D-glucoside의 신경세포 보호 효과에 대해 검토하였다. SH-SY5Y 신경세포에 $A{\beta}_{25-35}$ ($25{\mu}M$)를 처리하였을 때, 처리하지 않은 normal군에 비해 세포생존율이 유의적으로 감소하였다. 반면, kaempferol, quercetin 및 그 배당체들을 각각 처리하였을 때 $A{\beta}_{25-35}$만을 처리한 control군에 비해 유의적으로 세포생존율의 증가를 나타내었다. 또한, apoptosis에 관여하는 cleaved caspase9, Bcl-2-associated X protein (Bax) 단백질 발현을 측정한 결과, normal군에 비해 control군에서 유의적으로 cleaved caspase9 및 Bax 단백질 발현의 증가를 나타내어 $A{\beta}$ 유도 신경세포 손상으로 인한 apoptosis가 유발됨을 확인 하였으며, kaempferol, quercetin 및 그 배당체들의 처리 시 apoptosis 관련 단백질 발현이 감소함으로써 신경세포 보호 효능이 나타냄을 확인하였다. 이러한 결과는 kaempferol, quercetin 및 그 배당체들이 apoptosis 조절을 통해 신경세포 보호 효과를 나타내며, 신경세포 손상으로 인한 알츠하이머 질환을 예방하는 유용한 소재로써 사용 가능성이 있음을 보여준다.

• Nutrition Research and Practice
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• 제13권1호
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• pp.64-69
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• 2019

BACKGROUND/OBJECTIVES: Alzheimer's disease is a neurodegenerative disease that induces symptoms such as a decrease in motor function and cognitive impairment. Increases in the aggregation and deposition of amyloid beta protein ($A{\beta}$) in the brain may be closely correlated with the development of Alzheimer's disease. In this study, the effects of an adzuki bean extract on the aggregation of $A{\beta}$ were examined; moreover, the anti-Alzheimer's activity of the adzuki extract was examined. MATERIALS/METHODS: First, we undertook thioflavin T (ThT) fluorescence analysis and transmission electron microscopy (TEM) to evaluate the effect of an adzuki bean extract on $A{\beta}_{42}$ aggregation. To evaluate the effects of the adzuki extract on the symptoms of Alzheimer's disease in vivo, $A{\beta}_{42}$-overexpressing Drosophila were used. In these flies, overexpression of $A{\beta}_{42}$ induced the formation of $A{\beta}_{42}$ aggregates in the brain, decreased motor function, and resulted in cognitive impairment. RESULTS: Based on the results obtained by ThT fluorescence assays and TEM, the adzuki bean extract inhibited the formation of $A{\beta}_{42}$ aggregates in a concentration-dependent manner. When $A{\beta}_{42}$-overexpressing flies were fed regular medium containing adzuki extract, the $A{\beta}_{42}$ level in the brain was significantly lower than that in the group fed regular medium only. Furthermore, suppression of the decrease in motor function, suppression of cognitive impairment, and improvement in lifespan were observed in $A{\beta}_{42}$-overexpressing flies fed regular medium with adzuki extract. CONCLUSIONS: The results reveal the delaying effects of an adzuki bean extract on the progression of Alzheimer's disease and provide useful information for identifying novel prevention treatments for Alzheimer's disease.

• Journal of Microbiology and Biotechnology
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• 제23권2호
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• pp.161-166
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• 2013

At present, acetylcholinesterase (AChE) inhibitors are the first group of drugs to treat mild to moderate Alzheimer's disease (AD). Although beneficial in improving cognitive and behavioral symptoms, the effectiveness of AChE inhibitors has been questioned since they do not delay or prevent neurodegeneration in AD patients. Therefore, in the present study, in order to develop new and effective anti-AD agents from lichen products, both the AChE inhibitory and the neuroprotective effects were evaluated. The AChE inhibitory assay was performed based on Ellman's reaction, and the neuroprotective effect was evaluated by using the MTT method on injured PC12 cells. One AChE inhibitor ($IC_{50}$ = 27.1 ${\mu}g/ml$) was isolated by means of bioactivity-guided isolation from the extract of lichen-forming fungus Cladonia macilenta, which showed the most potent AChE inhibitory activity in previous screening experiment. It was then identified as biruloquinone by MS, and $^1H$- and $^{13}C$-NMR analyses. The inhibitory kinetic assay suggested that biruloquinone is a mixed-II inhibitor on AChE. Meanwhile, biruloquinone improved the viability of the $H_2O_2$- and ${\beta}$-amyloid-injured PC12 cells at 1 to 25 ${\mu}g/ml$. The protective effects are proposed to be related to the potent antioxidant activities of biruloquinone. These results imply that biruloquinone has the potential to be developed as a multifunctional anti- AD agent.

• 동의신경정신과학회지
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• 제12권2호
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• pp.173-183
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• 2001

Substance P can stimulate secretion of tumor necrosis $factor-\;{\alpha}\;(TNF-\;{\alpha}\;)$ from astrocytes stimulated with lipopolysaccharide (LPS). Here I report that Chilbogeum can modulate cytokines secretion from primary cultures of rat astrocytes. Chilbogeum $(10\;{\mu}g/ml)$ significantly inhibited the $TNF-\;{\alpha}$ secretion by astrocytes stimulated with LPS and Substance P. 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 Chilbogeum $(10,\;100\;{\mu}g/ml)$ to astrocytes stimulated with both LPS and Substance P decreased IL-1 secretion significantly. The secretion of $TNF-\;{\alpha}$ by LPS and Substance P in astrocytes was progressively inhibited with increasing amount of IL-1 neutralizing antibody. Upon stimulation from various agents, these cells adopt a reactive phenotype, a morphological hallmark in Alzheimer's disease (AD) pathology, during which they themselves may produce still more inflammatory cytokines. Chilbogeum $(10,\;100\;{\mu}g/ml)$ significantly inhibited the $TNF-\;{\alpha}$ secretion by CCF-STTG1 astrocytoma cells stimulated with $A\;{\beta}$ and IL-1. These results suggest that Chilbogeum may inhibit $TNF-\;{\alpha}$ secretion by inhibiting IL-1 secretion and that Chilbogeum has an antiinflammatory activity in AD brain.

• 한국식품영양과학회지
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• 제43권2호
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• pp.224-230
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• 2014

항암, 항염증 및 비만억제 등의 생리활성을 지닌 해조류는 최근 건강기능 식품, 기능성 화장품 그리고 의약품 산업 분야에서 미용과 건강식품 소재로 각광받고 있다. 본 연구에서는 10종의 갈조류 메탄올 추출물을 이용하여 1,1-diphenyl-2-picrylhydrazyl(DPPH) 라디칼 소거능과 아밀로이드 베타 단백질($A{\beta}$)의 신경독성에 대한 HT-22 신경세포 보호효과를 조사함으로써 천연물로부터 안전하고 새로운 신경세포 보호소재를 개발해내고자 한다. DPPH 라디칼 소거능의 경우 미역쇠를 포함한 8종의 갈조류에서는 비교적 낮은 활성산소 소거능을 보인 반면, 감태와 패에서 강력한 활성산소 소거능이 나왔다. $A{\beta}$의 신경독성에 대해 10종의 갈조류 추출물이 갖는 HT-22 신경세포 보호효과를 검증하기 위해 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) 분석과 APP, BACE1, iNOS 단백질의 발현양상 및 ERK1/2, p38, JNK1/2 단백질의 활성화 양상을 분석했다. MTT 분석 결과, $A{\beta}$의 신경독성으로부터 미역쇠가 $25{\mu}g/mL$의 농도에서 가장 효과적으로 세포를 보호하고 있는 것으로 나타났고, 알쏭이모자반, 불레기말, 바위수염, 짝잎모자반도 세포 보호효과가 있는 것으로 나타났다. 세포 보호효과가 있는 것으로 밝혀진 5종의 갈조류를 가지고 수행한 단백질 발현분석 결과, 미역쇠는 $A{\beta}$의 신경독성에 의해 HT-22 신경세포에서 발현되는 단백질인 BACE1과 iNOS의 발현을 저해하였다. 이는 미역쇠의 세포보호효과가 $A{\beta}$의 신경독성으로부터 일어난 ERK와 p38의 활성화에 연관된 세포신호전달 경로를 억제하는 것으로 보인다. 그러므로 특히 식용 갈조류인 미역쇠는 $A{\beta}$에 의해 유도된 신경독성에 대해서 신경세포 보호효과를 갖는 건강기능 식품 소재로서의 가치가 충분한 것으로 사료된다.

• Yonsei Medical Journal
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• 제59권9호
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• pp.1096-1106
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• 2018

Purpose: Alzheimer's disease (AD) is the sixth most common cause of death in the United States. MicroRNAs have been identified as vital players in neurodegenerative diseases, including AD. microRNA-128 (miR-128) has been shown to be dysregulated in AD. This study aimed to explore the roles and molecular mechanisms of miR-128 in AD progression. Materials and Methods: Expression patterns of miR-128 and peroxisome proliferator-activated receptor gamma ($PPAR-{\gamma}$) messenger RNA in clinical samples and cells were measured using RT-qPCR assay. $PPAR-{\gamma}$ protein levels were determined by Western blot assay. Cell viability was determined by MTT assay. Cell apoptotic rate was detected by flow cytometry via double-staining of Annexin V-FITC/PI. Caspase 3 and $NF-{\kappa}B$ activity was determined by a Caspase 3 Activity Assay Kit or $NF-{\kappa}B$ p65 Transcription Factor Assay Kit, respectively. Bioinformatics prediction and luciferase reporter assay were used to investigate interactions between miR-128 and $PPAR-{\gamma}$ 3'UTR. Results: MiR-128 expression was upregulated and $PPAR-{\gamma}$ expression was downregulated in plasma from AD patients and $amyloid-{\beta}$ $(A{\beta})-treated$ primary mouse cortical neurons (MCN) and Neuro2a (N2a) cells. Inhibition of miR-128 decreased $A{\beta}-mediated$ cytotoxicity through inactivation of $NF-{\kappa}B$ in MCN and N2a cells. Moreover, $PPAR-{\gamma}$ was a target of miR-128. $PPAR-{\gamma}$ upregulation attenuated $A{\beta}-mediated$ cytotoxicity by inactivating $NF-{\kappa}B$ in MCN and N2a cells. Furthermore, $PPAR-{\gamma}$ downregulation was able to abolish the effect of anti-miR-128 on cytotoxicity and $NF-{\kappa}B$ activity in MCN and N2a cells. Conclusion: MiR-128 inhibitor decreased $A{\beta}-mediated$ cytotoxicity by upregulating $PPAR-{\gamma}$ via inactivation of $NF-{\kappa}B$ in MCN and N2a cells, providing a new potential target in AD treatment.

• 한국축산식품학회지
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• 제33권2호
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• pp.258-267
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• 2013

각 돈피추출물의 수율과 단백질함량은 고분자 PS 처리구에서 높은 함량을 나타내었으며, 특히 단백질 함량은 저분자 LPS 처리구에 비해 유의적으로 높았고, 약 10배 정도의 높은 단백질 함량을 나타내었다(p<0.05). 항산화활성 측정결과 처리 농도가 증가할수록 높은 항산화 활성을 나타내었으며(p<0.05), 특히 고분자 PS 처리구에 비해 저분자 LPS 처리구에서 유의적으로 높은 효과를 나타내었다. ORAC 활성은 LPS 농도 1 mg/mL일 때, $141.39{\mu}M$ TE/g의 높은 활성을 나타내었다. 각 돈피추출물을 신경모세포종 SH-SY5Y 세포에 고농도로 처리한 결과 세포에 독성을 나타내지 않았다. 신경세포에 과산화수소를 처리하여 유발시킨 산화적 스트레스에 대한 PS와 LPS의 신경세포 보호효과를 확인한 결과, 모든 처리구에서 농도 의존적으로 세포 보호효과를 나타내었다. 특히 저분자인 LPS 처리구 농도 $100{\mu}g/mL$일 때, 86.45%의 세포생존율을 보였으며 $H_2O_2$ 대비 29.98%의 신경세포보호효과를 나타내었다. 독성 단백질인 $A{\beta}_{1-42}$를 처리하여 신경세포 보호효과를 확인한 결과, 고분자 PS 처리구보다는 저분자인 LPS 처리구 농도 $100{\mu}g/mL$일 때, 82.01%의 생존율을 보였으며 $A{\beta}_{1-42}$ 대비 14.38%의 신경세포보호효과를 나타내었다(p<0.05). AChE 저해효과를 확인해 본 결과, 고분자 PS 처리구에서는 거의 효과가 나타나지 않았으나, 저분자인 LPS 처리구에서는 농도 의존적으로 증가하는 경향을 나타내었으며, 농도 100 mg/mL일 때 33.62%의 높은 저해 효과를 나타내었다. 따라서 본 연구결과 돈피에서 분리한 3 kDa 이하의 저분자 효소분해물인 LPS는 높은 항산화 활성을 나타내었고, $H_2O_2$와 $A{\beta}_{1-42}$로 유발시킨 산화스트레스에 대한 신경세포 보호효과 및 AChE 저해 효과를 나타내어 향후 항산화 활성 및 신경세포보호를 위한 축산식품 소재로 이용 가능성이 있을 것으로 판단된다.

• 생명과학회지
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• 제34권7호
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• pp.509-519
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• 2024

선행연구에서 크릴 오일의 항산화 작용을 통한 Amyloid β로 저하된 설치류의 인지능과 기억력을 개선시킨다는 것을 확인하였으나 신경전달물질 등의 조절에 대한 유효성 확인과 지질 과산화와 혈중지질과의 연계성이 필요하여 본 연구를 진행하였다. Scopolamine으로 신경전달 체계를 교란시킨 ICR mice에서 크릴오일 섭취에 따른 수동회피, 수중미로, 신물질 탐색 등의 행동시험을 실시하여 인지 및 기억력 개선에 대한 유효성과 뇌 조직에서의 acetylcholine 수준과 acetylcholinesterase의 활성 변화와 함께 지질 과산화와 혈중지질 수준 그리고 신경세포 증식인자의 발현량에 대한 변화를 조사하였다. 그 결과 scopolamine 처리군에 비해 크릴 오일 섭취로 인한 수동회피시험에서의 정체시간 지연과 수중미로시험에서의 탈출지연시간 단축을 확인하여 인지 및 기억력을 개선을 확인하였다. 또한, acetylcholine 수준이 scopolamine 처리군 보다 증가되는 것을 확인하였고 여기에는 acetylcholine esterase의 활성 감소가 동반되었다. Scopolamine을 처리한 신경세포주에서도 크릴 오일 처리에 따라 acetylcholinesterase의 활성이 감소되는 것을 확인하였다. 또한, 크릴 오일이 지질 과산화 억제에 의한 malondialdehyde 생성 수준을 감소시키는 것이 혈중 중성지질, 콜레스테롤과 LDL-C 등의 저하와 HDL-C의 상승과 연관되는 것으로 확인되며 CREB의 활성 증가를 통해 BDNF의 상승으로 신경세포 증식인자 발현량 증가에 대한 효과가 있는 것으로 확인되었다. 따라서, 본 연구를 통해 크릴 오일은 뇌 조직 내 acetylcholine 등 신경전달물질 수준의 개선, 지질 과산화 억제 등을 통한 혈중지질 개선과 신경세포 증식 인지기능 및 기억력 개선 효과를 가지는 것으로 확인하였다.