• Title/Summary/Keyword: Alzheimer's disease(AD)

Search Result 452, Processing Time 0.033 seconds

Isolation and Quantitative Analysis of BACE1 Inhibitory Compounds from Cirsium maackii Flower

  • Bhatarrai, Grishma;Seong, Su Hui;Jung, Hyun Ah;Choi, Jae Sue
    • Natural Product Sciences
    • /
    • v.25 no.4
    • /
    • pp.326-333
    • /
    • 2019
  • The purpose of our study was to evaluate anti-AD potential of Cirsium maackii flowers. MeOH extract, CH2Cl2, EtOAc, and n-BuOH fraction of this flower notably inhibited BACE1 (IC50 = 76.47 ± 1.66, 22.98 ± 1.45, 8.65 ± 0.63, and 72.47 ± 3.04 ㎍/mL, respectively). β-amyrenone (49.70 mg) (1), lupeol acetate (1.43 g) (2), lupeol (1.22 g) (3), lupenone (23.70 mg) (4), β-sitosterol (1.01 g) (6), and β-sitosterol glucoside (13.00 mg) (7) from CH2Cl2, apigenin (100.20 mg) (8), luteolin (19.00 mg) (9), apigenin 7-O-glucuronide methyl ester (21.30 mg) (14), and tracheloside (53.70 mg) (5) from EtOAc, apigenin 5-O-glucoside (11.00 mg) (10), luteolin 5-O-glucoside (11.00 mg) (11) and apigenin 7-O-glucuronide (91.00 mg) (12) from n-BuOH, and luteolin 7-O-glucuronide (22.00 mg) (13) from H2O fraction were isolated. HPLC showed high levels of 8, 9 and 12 in MeOH extract (33.07 ± 0.07, 31. 44 ± 0.17 and 16.89 ± 0.33 mg/g, respectively), EtOAc (161.01 ± 1.78, 96.93 ± 0.34 and 73.38 ± 0.06 mg/g, respectively), and n-BuOH fraction (32.18 ± 0.33, 44.31 ± 0.32 and 105.94 ± 0.36 mg/g, respectively). Since, 3 and 9 are well-known BACE1 inhibitors, the anti-AD activity of C. maackii flower might be attributable to their presence.

Effects Amyloid Beta Peptide on the Inflammatory Response in Neuronal Cells (베타아밀로이드가 신경세포에 미치는 염증 작용 연구)

  • Jang, Seon-A;Koo, Hyun Jung;Kang, Se Chan;Sohn, Eun-Hwa;Namkoong, Seung
    • KSBB Journal
    • /
    • v.28 no.4
    • /
    • pp.230-237
    • /
    • 2013
  • Amyloid ${\beta}$ peptide (A${\beta}$) still best known as a molecule to cause Alzheimer's disease (AD). AD is characterized by the accumulation and deposition of A${\beta}$ within the brain, leading to neuronal cell loss and perturbation of synaptic function by causing free radical formation, inflammation and apoptosis. We investigated the inflammatory action of A${\beta}$ on two types of brain cells, neuronal cells (SH-SY5Y) and neuroglia cells (C6), and its mechanism. We measured the production of NO-iNOS, TNF-${\alpha}$, and ICAM-1 using RT-PCR and Western blot analysis less than the concentration of cytotoxic effects (> 70% survivability). A${\beta}$ had no effect on the production of NO and TNF-${\alpha}$, but significantly increases of iNOS and ICAM-1. Based on this, we suggest that the inflammatory effect of A${\beta}$ results from the action of ICAM-1 in neuronal cells, rather than the release of inflammatory mediators such as NO and TNF-${\alpha}$ in neuroglia cells. In addition, we confirmed whether p53 was related to the action of A${\beta}$ by using SH-SY5Y ($p53^{-/-}$) dominant cells. Neither the expression of p53 nor the cytotoxicity of SH-SY5Y ($p53^{-/-}$) cells were directly affected by A${\beta}$. However, ICAM-1 was not expressed in SH-SY5Y ($p53^{-/-}$) cells. This means that p53- independent pathway exists in the expression of ICAM-1 by A${\beta}$ while p53 plays a role as an on-and-off switch.

Protective Effects of Combination of Carthamus tinctorius L. Seed and Taraxacum coreanum on Scopolamine-induced Memory Impairment in Mice (홍화씨와 흰민들레 복합물의 Scopolamine 유도 기억력 손상에 대한 보호 효과)

  • Kim, Ji Hyun;He, Mei Tong;Kim, Min Jo;Park, Chan Hum;Lee, Jae Yang;Shin, Yu Su;Cho, Eun Ju
    • Korean Journal of Medicinal Crop Science
    • /
    • v.28 no.2
    • /
    • pp.85-94
    • /
    • 2020
  • Background: Alzheimer's disease (AD) is caused by various factors, such as cholinergic dysfunction, regulation of neurotrophic factor expression, and accumulation of amyloid-beta. We investigated whether or not a combination of Carthamus tinctorius L. seed and Taraxacum coreanum (CT) has a protective effect on scopolamine-induced memory impairment in a mouse model. Methods and Results: Mice were orally pretreated with CT (50, 100 and 200 mg/kg/day) for 14 days, and scopolamine (1 mg/kg/day) was injected intraperitoneally before subjecting them to behavior tests. CT-administered mice showed better novel object recognition and working memory ability than scopolamine-treated control mice. In T-maze and Morris water maze tests, CT (100 and 200 mg/kg/day) significantly increased space perceptive ability and occupancy to the target quadrant, respectively. In addition, 100 and 200 mg/kg/day of CT attenuated cholinergic dysfunction through inhibition of butyryl cholinesterase in brain tissue. Furthermore, CT-administered mice showed higher cyclic adenosine monophosphate-response element-binding protein (CREB) levels and lower amyloid precursor protein (APP) levels compared to scopolamine-treated control mice. Conclusions: CT improved scopolamine-induced memory impairment through inhibition of cholinergic dysfunction, up-regulation of CREB, and down-regulation of APP. Therefore, CT could be a useful therapeutic agent for AD with protective effects on cognitive impairment.

Bi-flavonoids are Superior to Mono-flavonoid in Inhibiting Amyloid-${\beta}$ Toxicity and Fibrillogenesis through Accumulating Nontoxic Oligomer-like Structures

  • Merlin Jayalal, L.P.
    • Journal of Integrative Natural Science
    • /
    • v.5 no.2
    • /
    • pp.107-119
    • /
    • 2012
  • Polymerization of monomeric amyloid-${\beta}$ peptides ($A{\beta}$) into soluble oligomers and insoluble fibrils is one of the major pathways triggering the pathogenesis of Alzheimer's disease (AD). Using small molecules to prevent the polymerization of $A{\beta}$ peptides can, therefore, be an effective therapeutic strategy for AD. In this study, we investigated the effects of mono- and bi-flavonoids on $A{\beta}42$ toxicity and fibrillogenesis and found that the bi-flavonoid, taiwaniaflavone (TF) effectively and specifically inhibits $A{\beta}$ toxicity and fibrillogenesis. Compared to TF, the mono-flavonoid apigenin (AP) is less effective and less specific. Our data showed that differential effects of the mono- and bi-flavonoids on $A{\beta}$ fibrillogenesis correlate with their varying cytoprotective efficacies. We also found that other bi-flavonoids, namely 2',8"-biapigenin, amentoflavone, and sumaflavone, can also effectively inhibit $A{\beta}$ toxicity and fibrillogenesis, implying that the participation of two mono-flavonoids in a single bi-flavonoid molecule enhanced their activity. Bi-flavonoids, while strongly inhibited $A{\beta}$ fibrillogenesis, accumulated nontoxic $A{\beta}$ oligomeric structures, suggesting that these are off-pathway-oligomers. Moreover, TF abrogated the toxicity of preformed $A{\beta}$ oligomers and fibrils, indicating that TF and other bi-flavonoids may also reduce the toxicity of toxic $A{\beta}$ species. Altogether, our data clearly show that bi-flavonoids, possibly due to the possession of two $A{\beta}$ binders separated by an appropriate size linker, are likely to be promising therapeutics to suppress $A{\beta}$ toxicity.

Protective effects of N,4,5-trimethylthiazol-2-amine hydrochloride on hypoxia-induced β-amyloid production in SH-SY5Y cells

  • Han, A Reum;Yang, Ji Woong;Na, Jung-Min;Choi, Soo Young;Cho, Sung-Woo
    • BMB Reports
    • /
    • v.52 no.7
    • /
    • pp.439-444
    • /
    • 2019
  • Although hypoxic/ischemic injury is thought to contribute to the incidence of Alzheimer's disease (AD), the molecular mechanism that determines the relationship between hypoxia-induced ${\beta}$-amyloid ($A{\beta}$) generation and development of AD is not yet known. We have now investigated the protective effects of N,4,5-trimethylthiazol-2-amine hydrochloride (KHG26702), a novel thiazole derivative, on oxygen-glucose deprivation (OGD)-reoxygenation (OGD-R)-induced $A{\beta}$ production in SH-SY5Y human neuroblastoma cells. Pretreatment of these cells with KHG26702 significantly attenuated OGD-R-induced production of reactive oxygen species and elevation of levels of malondialdehyde, prostaglandin $E_2$, interleukin 6 and glutathione, as well as superoxide dismutase activity. KHG26702 also reduced OGD-R-induced expression of the apoptotic protein caspase-3, the apoptosis regulator Bcl-2, and the autophagy protein becn-1. Finally, KHG26702 reduced OGD-R-induced $A{\beta}$ production and cleavage of amyloid precursor protein, by inhibiting secretase activity and suppressing the autophagic pathway. Although supporting data from in vivo studies are required, our results indicate that KHG26702 may prevent neuronal cell damage from OGD-R-induced toxicity.

Age-Dependent Sensitivity to the Neurotoxic Environmental Metabolite, 1,2-Diacetylbenzene

  • Hoang, Ngoc Minh Hong;Kim, Sungjin;Nguyen, Hai Duc;Kim, Minjo;Kim, Jin;Kim, Byoung-Chul;Park, Daeui;Lee, Sujun;Yu, Byung Pal;Chung, Hae Young;Kim, Min-Sun
    • Biomolecules & Therapeutics
    • /
    • v.29 no.4
    • /
    • pp.399-409
    • /
    • 2021
  • 1,2-Diacetylbenzene (DAB) is a metabolite of 1,2-diethylbenzene, which is commonly used in the manufacture of plastics and gasoline. We examined the neurotoxic effects of DAB in young and old rats, particularly its effects on hippocampus. Previously, we reported DAB impairs hippocampal neurogenesis but that the underlying mechanism remained unclear. In this study, we evaluate the toxicities exhibited by DAB in the hippocampi of 6-month-old (young) and 20-month-old (old) male SD rats by treating animals intraperitoneally with DAB at 3 mg/kg/day for 1 week. Hippocampal areas were dissected from brains and RNA was extracted and subjected to RNA-seq analysis. RNA results showed animals exhibited age-dependent sensitivity to the neurotoxic effects of DAB. We observed that inflammatory pathways were up-regulated in old rats but that metabolism- and detoxification-related pathways were up-regulated in young rats. This result in old rats, especially upregulation of the TREM1 signaling pathway (an inflammatory response involved in Alzheimer's disease (AD)) was confirmed by RT-PCR. Our study results provide a better understanding of age-dependent responses to DAB and new insight into the association between DAB and AD.

Neuroprotective effects of three flavonoids from Acer okamotoanum against neurotoxicity induced by amyloid beta in SH-SY5Y cells

  • Ji Hyun Kim;Sanghyun Lee;Eun Ju Cho
    • Korean Journal of Agricultural Science
    • /
    • v.49 no.2
    • /
    • pp.227-237
    • /
    • 2022
  • Amyloid beta (Aβ) is produced from an amyloid precursor protein by the activation of the amyloidogenic pathway, and it is widely known to cause Alzheimer's disease (AD). In this study, we investigated the neuroprotective effects of three flavonoids, quercitrin, isoquercitrin, and afzelin, from Acer okamotoanum against Aβ-induced neurotoxicity in SH-SY5Y neuronal cells. Aβ25-35 treatments resulted in decreased cell viability and increased levels of nuclei condensation and fragmentation. However, an isoquercitrin treatment dose-dependently increased cell viability and decreased nuclei condensation and fragmentation levels. SH-SY5Y cells treated with Aβ25-35 showed increased reactive oxygen species (ROS) production compared to that from cells not treated with Aβ25-35. However, treatment with the three flavonoids significantly inhibited ROS production compared to an Aβ25-35-treated control group, indicating that the three flavonoids blocked neuronal oxidative stress. For a closer examination of the neuroprotective mechanisms, we measured the expressions of the non-amyloidogenic pathway-related proteins of a disintegrin and metalloprotease 10 (ADAM10) and the tumor necrosis factor-α converting enzyme (TACE). An isoquercitrin treatment enhanced the expressions of ADAM10 compared to the control group. In addition, the three flavonoids activated the non-amyloidogenic pathway via the upregulation of TACE. In conclusion, we demonstrated neuroprotective effects of three flavonoids from A. okamotoanum, in particular isoquercitrin, on neurotoxicity by the regulation of the non-amyloidogenic pathway in Aβ25-35-treated SH-SY5Y cells. Therefore, we suggest that flavonoids from A. okamotoanum may have some potential as therapeutics of AD.

Overexpression of TMP21 Could Induce not only Downregulation of TrkA/ERK Phosphorylation but also Upregulation of p75NTR/RhoA Expression on NGF Receptor Signaling Pathway (γ-Secretase 활성억제단백질인 TMP21의 과발현이 신경세포주에서 NGF 수용체 신호전달과정에 미치는 영향)

  • Choi, Sun-Il;Jee, Seung-Wan;Her, Youn-Kyung;Kim, Ji-Eun;Nam, So-Hee;Hwang, In-Sik;Lee, Hye-Ryun;Goo, Jun-Seo;Lee, Young-Ju;Lee, Eon-Pil;Choi, Hae-Wook;Kim, Hong-Sung;Lee, Jae-Ho;Jung, Young-Jin;Lee, Su-Hae;Shim, Sun-Bo;Hwang, Dae-Youn
    • Journal of Life Science
    • /
    • v.21 no.8
    • /
    • pp.1134-1141
    • /
    • 2011
  • Transmembrane protein 21 (TMP21) is a member of the p24 cargo protein family and has been shown to modulate ${\alpha}$-secretase-mediated A${\beta}$ production which was specifically observed in the brains of subjects with Alzheimer's disease (AD). In order to investigate whether TMP21 could affect nerve growth factor (NGF) receptor signaling pathway, the alteration of NGF receptors and their downstream proteins were detected in TMP21 over-expressed cells. CMV/hTMP21 vector used in this study was successfully expressed into TMP21 proteins in B35 cells after lipofectamin transfection. Expressed TMP21 proteins induced the down-regulation of ${\gamma}$-secretase complex components including Presenlin-1 (PS-1), PS-2, Nicastrin (NST), Pen-2 and APH-1. Also, the expression level of NGF receptor $p75^{NTR}$ and RhoA were significantly higher in CMV/hTMP21 transfectants than vehicle transfectants, while their levels returned to vehicle levels after NGF treatment. However, the phosphorylation of NGF receptor TrkA was dramtically decreased in NGF No-treated CMV/hTMP21 transfectants compared with vehicle transfectants, and increased in NGF treated CMV/hTMP21 transfectants. In TrkA downstream signaling pathway, the phosphorylation level of ERK was also decreased in CMV/hTMP21 transfectants, while the phosphorylation of Akt was increased in the same transfectants. Furthermore, NGF treatment induced the increase of phosphorylation level of Akt and ERK in CMV/hTMP21 transfectants. Therefore, these results suggested that over-expression of TMP21may simultaneously induce the up-regulation of $p75^{NTR}$/RhoA expression and the down-regulation of TrkA/ERK phosphorylation through the inhibition of ${\gamma}$-secretase activity.

Application of False Discovery Rate Control in the Assessment of Decrease of FDG Uptake in Early Alzheimer Dementia (조기 알츠하이머 치매의 뇌포도당 대사 감소 평가에서 오류발견률 조절법의 적용)

  • Lee, Dong-Soo;Kang, Hye-Jin;Jang, Myung-Jin;Cho, Sang-Soo;Kang, Won-Jun;Lee, Jae-Sung;Kang, Eun-Joo;Lee, Kang-Uk;Woo, Jong-In;Lee, Myung-Chul
    • The Korean Journal of Nuclear Medicine
    • /
    • v.37 no.6
    • /
    • pp.374-381
    • /
    • 2003
  • Purpose: Determining an appropriate thresholding is crucial for PDG PET analysis since strong control of Type I error could fail to find pathological differences between eariy Alzheimer' disease (AD) patients and healthy normal controls. We compared the SPM results on FDG PET imaging of early AD using uncorrected p-value, random-field based corrected p-value and false discovery rate (FDR) control. Materials and Methods: Twenty-eight patients ($66{\pm}7$ years old) with early AD and 18 age-matched normal controls ($68{\pm}6$ years old) underwent FDG brain PET. To identify brain regions with hypo-metabolism in group or individual patient compared to normal controls, group images or each patient's image was compared with normal controls usingthe same fixed p-value of 0.001 on uncorrected thresholding, random-field based corrected thresholding and FDR control. Results: The number of hypo-metabolic voxels was smallest in corrected p-value method, largest in uncorrected p-value method and intermediate in FDG thresholding in group analysis. Three types of result pattern were found. The first was that corrected p-value did not yield any voxel positive but FDR gave a few significantly hypometabolic voxels (8/28, 29%). The second was that both corrected p-value and FDR did not yield any positive region but numerous positive voxels were found with the threshold of uncorrected p-values (6/28, 21%). The last was that FDR was detected as many positive voxels as uncorrected p-value method (14/28, 50%). Conclusions FDR control could identify hypo-metaboiic areas in group or individual patients with early AD. We recommend FDR control instead of uncorrected or random-field corrected thresholding method to find the areas showing hypometabolism especially in small group or individual analysis of FDG PET.

A Baseline Correction for Effective Analysis of Alzheimer’s Disease based on Raman Spectra from Platelet (혈소판 라만 스펙트럼의 효율적인 분석을 위한 기준선 보정 방법)

  • Park, Aa-Ron;Baek, Sung-June
    • Journal of the Institute of Electronics Engineers of Korea CI
    • /
    • v.49 no.1
    • /
    • pp.16-22
    • /
    • 2012
  • In this paper, we proposed a method of baseline correction for analysis of Raman spectra of platelets from Alzheimer's disease (AD) transgenic mice. Measured Raman spectra include the meaningful information and unnecessary noise which is composed of baseline and additive noise. The Raman spectrum is divided into the local region including several peaks and the spectrum of the region is modeled by curve fitting using Gaussian model. The additive noise is clearly removed from the process of replacing the original spectrum with the fitted model. The baseline correction after interpolating the local minima of the fitted model with linear, piecewise cubic Hermite and cubic spline algorithm. The baseline corrected models extract the feature with principal component analysis (PCA). The classification result of support vector machine (SVM) and maximum $a$ posteriori probability (MAP) using linear interpolation method showed the good performance about overall number of principal components, especially SVM gave the best performance which is about 97.3% true classification average rate in case of piecewise cubic Hermite algorithm and 5 principal components. In addition, it confirmed that the proposed baseline correction method compared with the previous research result could be effectively applied in the analysis of the Raman spectra of platelet.