• 한국생물물리학회:학술대회논문집
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• 한국생물물리학회 2003년도 정기총회 및 학술발표회
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• pp.47-47
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• 2003

The presenilin 1 (PS1) or PS2 is an essential component of the ${\gamma}$-secretase complex, which mediates the intramembrane proteolysis of selected type-I membrane, including the ${\beta}$-amyloid precursor protein (APP) to yield A${\beta}$. Familial Alzheimer's disease (FAD)-associated mutations in presenilins give rise to an increased production of a highly amyloidogenic A${\beta}$42. In addition to their well-documented proteolytic function, the presenilins play a role in calcium signaling. We have previously reported that presenilin FAD mutations cause highly consistent alterations in intracellular calcium signaling pathways, which include deficits in capacitative calcium entry (CCE), the refilling mechanism for depleted internal calcium stores. However, molecular basis for the presenilin-mediated modulation of CCE remains to be elucidated. In the present study, whole-cell patch clamp method was used to identify a specific calcium-permeable ion channel current(s) that is responsible for the CCE deficits associated with FAD-linked PS1 mutants. Unexpectedly, both voltage-activated and conventional store depletion-activated calcium currents I(CRAC), were absent in HEK293 cells, which were stably transfected either with wild-type or FAD mutant (L286V, M146L, and delta E9) forms of PS1. Recently, magnesium-nucleotide-regulated metal cation current, or I(MagNum), has been described and appears to share many common properties with I(CRAC) including calcium permeability and inhibitor sensitivity (e.g. 2-APB). We have detected I(MagNum) in all 293 cells tested. Interestingly, FAD mutant 293 cells developed only about half of currents compared to PS1 wild type cells.

• Molecules and Cells
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• 제37권11호
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• pp.767-776
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• 2014

Alzheimer's disease (AD) is clinically characterized with progressive memory loss and cognitive decline. Synaptic dysfunction is an early pathological feature that occurs prior to neurodegeneration and memory dysfunction. Mounting evidence suggests that aggregation of amyloid-${\alpha}$ ($A{\alpha}$) and hyperphosphorylated tau leads to synaptic deficits and neurodegeneration, thereby to memory loss. Among the established genetic risk factors for AD, the ${\varepsilon}4$ allele of apolipoprotein E (APOE) is the strongest genetic risk factor. We and others previously demonstrated that apoE regulates $A{\alpha}$ aggregation and clearance in an isoform-dependent manner. While the effect of apoE on $A{\alpha}$ may explain how apoE isoforms differentially affect AD pathogenesis, there are also other underexplored pathogenic mechanisms. They include differential effects of apoE on cerebral energy metabolism, neuroinflammation, neurovascular function, neurogenesis, and synaptic plasticity. ApoE is a major carrier of cholesterols that are required for neuronal activity and injury repair in the brain. Although there are a few conflicting findings and the underlying mechanism is still unclear, several lines of studies demonstrated that apoE4 leads to synaptic deficits and impairment in long-term potentiation, memory and cognition. In this review, we summarize current understanding of apoE function in the brain, with a particular emphasis on its role in synaptic plasticity and the underlying cellular and molecular mechanisms, involving low-density lipoprotein receptor-related protein 1 (LRP1), syndecan, and LRP8/ApoER2.

• 동의신경정신과학회지
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• 제16권1호
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• pp.81-96
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• 2005

This experiment was designed to investigate the effect of Dichroa febrifuga(DIF) on the Alzheimer’s disease. The effects of DIF extract on $IL-1{\beta}$, IL-6, $TNF-{\alpha}$ mRNA of THP-1 cell treated by $A{\beta}$ plus LPS and amyloid precursor proteins(APP), acetylcholinesterase(AChE), glial fibrillary acidic protein(GFAP) mRNA of PC-12 cell treated by $A{\beta}$ plus $rIL-1{\beta}$ and AChE activity of PC-12 cell lysate treated by $A{\beta}$ plus $rIL-1{\beta}$ and behavior of memory deficit mice induced by scopolamine and mice glucose, uric acid, AChE activity of memory deficit rats induced by scopolamine were investigated, respectively. The results were summarized as follows ; 1. DIF extract suppressed APP, AChE, GFAP mRNA in PC-12 cell treated by $A{\beta}$. 2. DIF extract suppressed $IL-1{\beta}$, IL-6, $TNF-{\alpha}$ mRNA in THP-1 cell treated by LPS. 3. DIF extract suppressed AChE activity in cell lysate of PC-12 cell treated by $A{\beta}$. 4. DIF extract increased glucose, decreased uric acid and AChE significantly in the serum of the memory deficit rats induced by scopolamine. 5. DIF 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 DIF extract might be usefully applied for prevention and treatment of Alzheimer’s disease and memory deficit.

• 동의신경정신과학회지
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• 제16권1호
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• pp.67-80
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• 2005

This experiment was designed to investigate the effect of Rheum palmatum(RHP) on the Alzheimer's disease. The effects of RHP extract on amyloid precursor proteins(APP), acetylcholinesterase(AChE), glial fibrillary acidic protein(GFAP) mRNA of PC-12 cell treated by $A{\beta}\;and\;IL-1{\beta},\;IL-6,\;TNF-{\alpha}$ mRNA of THP-1 cell treated by LPS and AChE activity of PC-12 cell lysate treated by $A {\beta}$and behavior of memory deficit rats induced by scopolamine and mice glucose, uric acid, AChE activity of memory deficit rats induced by scopolamine were investigated, respectively. The results were summarized as follows ; 1. RHP extract suppressed APP, AChE, GFAP mRNA in PC-12 cell treated by $A{\beta} $. 2. RHP extract suppressed $IL-1{\beta} $, IL-6 $TNF-{\alpha}$ mRNA in THP-1 cell treated by LPS. 3. RHP extract suppressed AChE activity in cell lysate of PC-12 cell treated by $A{\beta}$. 4. HP extract increased glucose, decreased uric acid and AChE significantly in the serum of the memory deficit rats induced by scopolamine. 5. RHP 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 RHP extract might be usefully applied for prevention and treatment of Alzheimer’s disease and memory deficit symptom.

• Biomolecules & Therapeutics
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• 제20권3호
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• pp.332-339
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• 2012

The components of Magnolia officinalis have well known to act anti-inflammatory, anti-oxidative and neuroprotective activities. These efficacies have been sold many products as nutritional supplement extracted from bark of Magnolia officinalis. Thus, to assess and compare neuroprotective effect in the nutritional supplement (Magnolia $Extract^{TM}$, Health Freedom Nutrition LLC, USA) and our ethanol extract of Magnolia officinalis (BioLand LTD, Korea), we investigated memorial improving and anti-Alzheimer's disease effects of extract products of Magnolia officinalis in a transgenic AD mice model. Oral pretreatment of two extract products of Magnolia officinalis (10 mg/kg/day in 0.05% ethanol) into drinking water for 3 months ameliorated memorial dysfunction and prevented $A{\beta}$ accumulation in the brain of Tg2576 mice. In addition, extract products of Magnolia officinalis also decreased expression of ${\beta}$-site APP cleaving enzyme 1 (BACE1), amyloid precursor protein (APP) and its product, C99. Although both two extract products of Magnolia officinalis could show preventive effect of memorial dysfunction and $A{\beta}$ accumulation, our ethanol extract of Magnolia officinalis (BioLand LTD, Korea) could be more effective than Magnolia $Extract^{TM}$ (Health Freedom Nutrition LLC, USA). Therefore, our results showed that extract products of Magnolia officinalis were effective for prevention and treatment of AD through memorial improving and anti-amyloidogenic effects via down-regulating ${\beta}$-secretase activity, and neuroprotective efficacy of Magnolia extracts could be differed by cultivating area and manufacturing methods.

• Parasites, Hosts and Diseases
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• 제49권3호
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• pp.213-219
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• 2011

This experiment was conducted to assess the changing patterns and relative values of acute phase proteins and inflammatory cytokines in experimental caprine coccidiosis. Eighteen newborn kids were allocated to 3 equal groups. Two groups, A and B, were inoculated with a single dose of $1{\times}10^3$ and$1{\times}10^5$sporulated oocysts of Eimeria arloingi, respectively. The third group, C, received distilled water as the control. Blood samples were collected from the jugular vein of each kid in both groups before inoculation and at days 7, 14, 21, 28, 35, and 42 post-inoculation (PI), and the levels of haptoglobin (Hp), serum amyloid A (SAA), TNF-${\alpha}$, and IFN-${\gamma}$ were measured. For histopathological examinations, 2 kids were selected from each group, euthanized, and necropsied on day 42 PI. Mean Hp concentrations in groups A and B (0.34 and 0.68 g/L) at day 7 PI were 3.2 and 6.3 times higher than the levels before inoculation. The mean SAA concentrations in groups A and B (25.6 and 83.5 ${\mu}g$/ml) at day 7 PI were 4.2 and 13.7 times higher than the levels before inoculation. The magnitude and duration of the Hp and SAA responses correlated well with the inoculation doses and the severity of the clinical signs and diarrhea in kids. These results were consistent with the histopathological features, which showed advanced widespread lesions in group B. In both groups, significant correlations were observed for TNF-${\alpha}$ and IFN-${\gamma}$ with SAA and Hp, respectively. In conclusion, Hp and SAA can be useful non-specific diagnostic indicators in caprine coccidiosis.

• 통합자연과학논문집
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• 제7권1호
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• pp.25-38
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• 2014

Amyloid-${\beta}$-peptide ($A{\beta}$) is important in the pathogenesis of Alzheimer's disease (AD). Calpain ($Ca^{2+}$-dependent protease) and caspase-8 (the initiating caspase for the extrinsic, receptor-mediated apoptosis pathway) have been implicated in $AD/A{\beta}$ toxicity. We found that $A{\beta}$ promoted degradation of calpastatin (the specific endogenous calpain inhibitor); calpastatin degradation was prevented by inhibitors of either calpain or caspase-8. The results implied a cross-talk between the two proteases and suggested that one protease was responsible for the activity of the other one. In neuron-like differentiated PC12 cells, calpain promotes active caspase-8 formation from procaspase-8 via the $A{\beta}$ and CD95 pathways, along with degradation of the procaspase-8 processing inhibitor caspase-8 (FLICE)-like inhibitory protein, short isoform (FLIPS). Inhibition of calpain (by pharmacological inhibitors and by overexpression of calpastatin) prevents the cleavage of procaspase-8 to mature, active caspase-8, and inhibits FLIPS degradation in the $A{\beta}$-treated and CD95-triggered cells. Increased cellular Ca2+ per se results in calpain activation but does not lead to caspase-8 activation or FLIPS degradation. The results suggest that procaspase-8 and FLIPS association with cell membrane receptor complexes is required for calpain-induced caspase-8 activation. The results presented here add to the understanding of the roles of calpain, caspase- 8, and CD95 pathway in $AD/A{\beta}$ toxicity. Calpain-promoted activation of caspase-8 may have implications for other types of CD95-induced cell damage, and for nonapoptotic functions of caspase-8. Inhibition of calpain may be useful for modulating certain caspase-8-dependent processes.

• Journal of Ginseng Research
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• 제46권3호
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• pp.464-472
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• 2022

Background: Gut microbiota influence the central nervous system through gut-brain-axis. They also affect the neurological disorders. Gut microbiota differs in patients with Alzheimer's disease (AD), as a potential factor that leads to progression of AD. Oral intake of Korean Red Ginseng (KRG) improves the cognitive functions. Therefore, it can be proposed that KRG affect the microbiota on the gut-brain-axis to the brain. Methods: Tg2576 were used for the experimental model of AD. They were divided into four groups: wild type (n = 6), AD mice (n = 6), AD mice with 30 mg/kg/day (n = 6) or 100 mg/kg/day (n = 6) of KRG. Following two weeks, changes in gut microbiota were analyzed by Illumina HiSeq4000 platform 16S gene sequencing. Microglial activation were evaluated by quantitative Western blot analyses of Iba-1 protein. Claudin-5, occludin, laminin and CD13 assay were conducted for Blood-brain barrier (BBB) integrity. Amyloid beta (Aβ) accumulation demonstrated through Aβ 42/40 ratio was accessed by ELISA, and cognition were monitored by Novel object location test. Results: KRG improved the cognitive behavior of mice (30 mg/kg/day p < 0.05; 100 mg/kg/day p < 0.01), and decreased Aβ 42/40 ratio (p < 0.01) indicating reduced Aβ accumulation. Increased Iba-1 (p < 0.001) for reduced microglial activation, and upregulation of Claudin-5 (p < 0.05) for decreased BBB permeability were shown. In particular, diversity of gut microbiota was altered (30 mg/kg/day q-value<0.05), showing increased population of Lactobacillus species. (30 mg/kg/day 411%; 100 mg/kg/day 1040%). Conclusions: KRG administration showed the Lactobacillus dominance in the gut microbiota. Improvement of AD pathology by KRG can be medicated through gut-brain axis in mice model of AD.

• 생명과학회지
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• 제20권3호
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• pp.444-452
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• 2010

본 연구의 목적은 PS-2 (N141I) 알츠하이머 형질전환 모델 생쥐를 대상으로 트레드밀 운동이 뇌의 세포질과 미토콘드리아의 $A{\beta}$-42, cytochrome c, SOD-1, 2 and Sirt-3 단백질 발현에 미치는 효과를 알아보는데 있다. 우선 알츠하이머 형질전환 생쥐를 Non-Tg-sedentary (n=5), Non-Tg-treadmill exercise (n=5) 집단과 Tg-sedentary (n=5), Tg-treadmill exercise (n=5) 집단으로 구분하고 트레드밀 운동을 통한 신경보호 효과를 검증하기 위해 Tg와 Non-Tg집단에 12주간 트레드밀 운동을 수행한 후 인지능력을 살펴보고 뇌의 세포질과 미토콘드리아의 $A{\beta}$-42, cytochrome c, anti-oxidant enzymes (SOD-1, SOD-2)와 Sirt-3 단백질을 분석하였다. 먼저 트레드밀운동은 Tg 집단에서 인지능력의 개선을 나타냈으며 미토콘드리아의 $A{\beta}$-42와 세포질의 cytochrome c 단백질의 감소와 항산화 효소인 SOD-1, SOD-2를 유의하게 증가시켰다. 게다가 트레드밀 운동은 모든 집단에서 Sirt-3 단백질의 발현을 증가시켰다. 따라서 트레드밀 운동은 인지능력의 향상과 세포 내 스트레스를 유발하는 $A{\beta}$-42를 억제시켜 알츠하이머 질환을 개선시킬 수 있는 효과적인 방법이라고 생각된다.

• Restorative Dentistry and Endodontics
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• 제31권6호
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• pp.437-444
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• 2006

본 연구에서는 법랑모세포 분화와 법랑질 형성에 연관이 있는 OD314 일명 Apin protein의 기능을 밝힐 목적으로, in-situ hybridization에 의한 OD314 mRNA 발현과 법랑모세포 세포주에서 OD314와 enamel matrix protein의 발현, 그리고 OD314 유전자를 과발현/억제시킬 수 있는 construct를 제작한 후 법랑질 형성 중에 OD314의 기능을 알아보고자 RT-PCR를 시행하여 다음과 같은 결과를 얻었다. 1. OD314 mRNA는 발생중인 상아모세포보다 법랑모세포에서 강하게 발현되었다. 2. Tuftelin은 석회화 결정이 형성되는 14일까지 발현이 지속되고, 그 이후부터 점차 감소하였다. Amelogenin과 enamelin은 7일부터 그 발현이 점점 감소하였다. 3. U6-OD314 siRNA construct를 이용하여 transfection한 법랑모세포 세포주는 OD314와 tuftelin, MMP20 mRNA 발현이 감소하였으며, CMV-OD3l4를 transfection하여 OD314의 과발현을 유도한 경우에는 OD3l4와 MMP20 mRNA의 발현이 뚜렷이 증대되었다. 이 결과는 OD314가 법랑모세포의 분화와 법랑질의 형성 그리고 석회화 과정에 중요한 역할을 하는 새로운 인자임을 시사한다.