인지기능 저하 노인에서 베타아밀로이드 양전자방출단층촬영의 효용성에 대한 증례군 보고 및 고찰

오지훈,나세정,이승엽,이해국,이경욱,권용실,안류연,이성용,이정태 대한노인정신의학회 2016 노인정신의학 Vol.20 No.1

The aim was to evaluate the diagnostic utility of beta-amyloid positron emission tomography (PET) in elderly patients with cognitive impairment in the clinical setting. Five subjects underwent beta-amyloid PET imaging to explore the cerebral beta-amyloid deposition. The two male patients with minor neurocognitive disorder due to Alzheimer’s disease, who displayed similar degree of cognitive impairment and medial temporal atrophy but different in apolipoprotein E4 status, both showed negative for beta-amyloid PET. On the other hand, a female major neurocognitive disorder due to probable Alzheimer’s disease patient was tested positive for beta-amyloid PET, with increased beta-amyloid density in frontal and parietal lobes. Beta-amyloid PET was also used for the differential diagnosis of neurocognitive disorder from other psychiatric disorders in two elderly patients. The results were negative but assisted the diagnositic confirmation. A female patient was determined to be a case of late-onset schizophrenia and a male patient was determined as delirium due to minor traumatic brain injury, persistent. Beta-amyloid PET imaging was able to demonstrate cerebral beta-amyloid deposition in major neurocognitive disorder due to probable Alzheimer’s disease in visual scale. However, further studies are needed for its clinical utility in the minor neurocognitive disorders. Moreover, beta-amyloid PET imaging may provide additional information in diagnosing primary psychiatric disorders with new onset in the old age.

Effect of Mycelial Extract of Clavicorona pyxidata on the Production of Amyloid $\beta$-Peptide and the Inhibition of Endogenous $\beta$-Secretase Activity in vitro

Lee, Tae-Hee,Park, Young-Il,Han, Yeong-Hwan The Microbiological Society of Korea 2006 The journal of microbiology Vol.44 No.6

Amyloid $\beta$-peptide (A$\beta$), which is a product of the proteolytic effect of $\beta$-secretase (BACE) on an amyloid precursor protein, is closely associated with Alzheimer's disease (AD) pathogenesis. There is sufficient evidence to suggest that a BACE inhibitor may reduce A$\beta$ levels, thus decreasing the risk of AD. In a previous study, an extract of Clavicorona pyxidata DGUM 29005 mycelia was found to inhibit the production of a soluble $\beta$-amyloid precursor protein (s$\beta$APP), A$\beta$, and BACE in neuronal cell lines. We sought to determine whether this mycelial extract exerts the same effect in human rhabdomyosarcoma A-204 and rat pheochromocytoma PC-12 cells. We found that the production of A$\beta$ decreased in a dose-dependent manner in the presence of the mycelial extract and that the concentration of A$\beta$ never exceeded $50{\mu}g/ml$. The presence of sAPP was detected in every culture medium to which the mycelial extract had been added and its concentration remained the same, regardless of the concentration of the extract used. Endogenous $\beta$-secretase activity in A-204 and PC-12 cellular homogenates also decreased in the presence of this extract. These cells, in culture, were not susceptible to the cytotoxic activity of the mycelial extract.

In vitro에서 β-site amyloid precursor protein-cleaving enzyme 활성과 amyloid β protein 생산에 대한 총명탕가미방(聰明湯加味方)의 효과

임정화,정인철,임종순,김승형,이상룡,Lim, Jung-Hwa,Jung, In-Chul,Lim, Jong-Soon,Kim, Seung-Hyung,Lee, Sang-Ryong 대한한방신경정신과학회 2010 동의신경정신과학회지 Vol.21 No.2

Objectives : This experiment was designed to investigate the effect of Chongmyung-Tang Prescription Combination(CmTP-$C_{1-10}$) extract on the production of amyloid $\beta$ protein and $\beta$-site amyloid precursor protein-cleaving enzyme(BACE) activity. Methods : The effect of CmTP-$C_{1-10}$ extract on expression of APP mRNA, BACE2 mRNA in BV2 microglia cell line treated by lipopolysacchride(LPS) and amyloid $\beta$ protein fragment(A$\beta$ fragment) were investigated. The effect of CmTP-$C_{1-10}$ extract on production of amyloid $\beta$ protein(A$\beta$) in BV2 microglia cell line treated by LPS and A$\beta$ fragment were investigated. The effect of CmTP-$C_{1-10}$ extract on BACE activity were investigated. Results : 1. CmTP-$C_9$ extract the most significantly suppressed the expression of APP mRNA, BACE2 mRNA in BV2 microglia cell line treated by LPS and A$\beta$ fragment. 2. CmTP-$C_9$ extract significantly suppressed the production of A$\beta$ in BV2 microglia cell line treated by LPS and A$\beta$ fragment. 3. CmTP-$C_9$ extract the most significantly inhibited BACE activity. Conclusions : These results suggest that CmTP-$C_9$ may be effective for the prevention and treatment of Alzheimer's Disease. Investigation into clinical use of CmTP-$C_9$ for Alzheimer's Disease is suggested for future research.

Electrochemical immunoassay for amyloid-beta 1–42 peptide in biological fluids interfacing with a gold nanoparticle modified carbon surface

Diba, Farhana Sharmin,Kim, Suhee,Lee, Hye Jin Elsevier 2017 CATALYSIS TODAY - Vol.295 No.-

<P><B>Abstract</B></P> <P>An electrochemical immunosensor involving the formation of a surface sandwich complex on a gold nanoparticle (NP) modified screen printed carbon electrode (SPCE) is demonstrated for the femtomolar detection of amyloid-beta 1–42 peptide (Aβ) in both serum and plasma. Both bioreceptors forming the assay are highly selective antibodies for Aβ, namely antiAβ (12F4) and (1E11) which possess different binding sites for the Aβ peptide. In order to improve the sensing performance for complex biological fluidic matrix analysis, different mixed monolayers of thiol modified polyethylene glycol (PEG) and mercaptopropionic acid (MPA) were self-assembled onto the Au NP-SPCE followed by tethering antiAβ (12F4) to MPA using a heterobifunctional cross linker. Surface sandwich complexes of antiAβ (12F4)/Aβ/antiAβ (1E11)-ALP were then formed via sequential adsorption with the latter antiAβ (1E11) conjugated to alkaline phosphatase (ALP) enzyme. The reaction of surface immobilized ALP with the substrate, 4-amino phenyl phosphate (APP), generated voltammetric detection signals that linearly increased as a function of Aβ concentration. Differential pulse voltammetry was applied to establish a lowest detectable concentration of 100 fM of Aβ with a linear response range from 100 fM to 25 pM. Following optimization, the immunoassay platform was applied in diluted human serum and plasma samples to determine the native concentration of Aβ and the results were validated using a commercially available ELISA test.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A highly sensitive and sensitive sandwich assay for amyloid-beta 1–42 peptide (Aβ). </LI> <LI> Formation of antiAβ (12F4)/Aβ/antiAβ (1E11)-ALP surface sandwich complex. </LI> <LI> Use of a mixed monolayer for sensors surface to improve non-specific adsorption. </LI> <LI> Direct analysis of Aβ in diluted human serum and plasma samples. </LI> <LI> A lowest detectable concentration of 100 fM Aβ with dynamic range of 0.1–25 pM. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>A new electrochemical-based surface sandwich assay constructed on Au nanoparticles deposited on a screen printed carbon electrode was developed for the femtomolar detection of unmodified amyloid-beta 1–42 (Aβ) in serum and plasma samples at native concentrations.</P> <P>[DISPLAY OMISSION]</P>

Protective Effect of Citrate against $A{\beta}$-induced Neurotoxicity in PC12 Cells

Yang, Hyun-Duk,Son, Il-Hong,Lee, Sung-Soo,Park, Yong-Hoon The Korean Society of Toxicogenomics and Toxicopro 2008 Molecular & cellular toxicology Vol.4 No.2

Formation of ${\beta}$-amyloid $(A{\beta})$ fibrils has been identified as one of the major characteristics of Alzheimer's disease (AD). Inhibition of $A{\beta}$ fibril formation in the CNS would be attractive therapeutic targets for the treatment of AD. Several small compounds that inhibit amyloid formation or amyloid neurotoxicity in vitro have been known. Citrate has surfactant function effect because of its molecular structure having high anionic charge density, in addition to the well-known antibacterial and antioxidant properties. Therefore, we hypothesized that citrate might have the inhibitory effect against $A{\beta}$ fibril formation in vitro and have the protective effect against $A{\beta}$-induced neurotoxicity in PC12 cells. We examined the effect of citrate against the formation of $A{\beta}$ fibrils by measuring the intensity of fluorescence in thioflavin-T (Th-T) assay of between $A{\beta}_{25-35}$ groups treated with citrate and the control with $A{\beta}_{25-35}$ alone. The neuroprotective effect of citrate against $A{\beta}$-induced toxicity in PC12 cells was investigated using the WST-1 assay. Fluorescence spectroscopy showed that citrate inhibited dose-dependently the formation of $A{\beta}$ fibrils from ${\beta}$-amyloid peptides. The inhibition percentages of $A{\beta}$ fibril formation by citrate (1, 2.5, and 5 mM) were 31%, 60%, and 68% at 7 days, respectively in thioflavin-T (Th-T) assay. WST-1 assay revealed that the toxic effect of $A{\beta}_{25-35}$ was reduced, in a dose-dependent manner to citrate. The percentages of neuroprotection by citrate (1, 2.5, and 5 mM) against $A{\beta}-induced$ toxicity were 19%, 31 %, and 34%, respectively. We report that citrate inhibits the formation of $A{\beta}$ fibrils in vitro and has neuroprotective effect against $A{\beta}$-induced toxicity in PC12 cells. Neuroprotective effects of citrate against $A{\beta}$ might be, to some extent, attributable to its inhibition of $A{\beta}$ fibril formation. Although the mechanism of anti-amyloidogenic activity is not clear, the possible mechanism is that citrate might have two effects, salting-in and surfactant effects. These results suggest that citrate could be of potential therapeutic value in Alzheimer's disease.

<i>Uncaria rhynchophylla</i> ameliorates amyloid beta deposition and amyloid beta-mediated pathology in 5XFAD mice

Shin, Soo Jung,Jeong, Yuon,Jeon, Seong Gak,Kim, Sujin,Lee, Seong-kyung,Choi, Hong Seok,Im, Cheong Su,Kim, Seong Hee,Kim, Soo Hwan,Park, Jae Ho,Kim, Jin-il,Kim, Jwa-Jin,Moon, Minho Elsevier 2018 Neurochemistry International Vol.121 No.-

<P><B>Abstract</B></P> <P>One of the pathological hallmarks of Alzheimer's disease (AD) is the abnormal aggregation of amyloid beta (Aβ) peptides. <I>Uncaria rhynchophylla</I> (UR), one of the <I>Uncaria</I> species, has long been used to treat neurodegenerative disease. In particular, it has been reported that UR inhibits aggregation of Aβ <I>in vitro.</I> However, little is known about the histological effects of UR treatment on Aβ pathology in AD animal models. In the present study, we investigated the effect of UR on Aβ aggregation, Aβ-mediated pathologies and adult hippocampal neurogenesis in the brain of 5XFAD mice. First, using the thioflavin T assay and amyloid staining, we demonstrated that UR treatment effectively inhibited Aβ aggregation and accumulation in the cortex and subiculum. Second, immunofluorescence staining showed that administration of UR attenuated gliosis and neurodegeneration in the subiculum and cortex. Third, UR treatment ameliorated impaired adult hippocampal neurogenesis. The present results indicate that UR significantly alleviates Aβ deposition and Aβ-mediated neuropathology in the brain in 5XFAD mice, suggesting the potency of UR as a preventive and therapeutic agent for AD.</P> <P><B>Highlights</B></P> <P> <UL> <LI> <I>Uncaria rhynchophylla</I> (UR) inhibited Aβ aggregation and accumulation. </LI> <LI> UR alleviated neuroinflammation induced by Aβ. </LI> <LI> Treatment of UR relieved synaptic and neuronal loss in AD mice. </LI> <LI> UR attenuated impaired hippocampal neurogenesis induced by Aβ. </LI> </UL> </P>

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

Merlin Jayalal, L.P. The Basic Science Institute Chosun University 2012 조선자연과학논문집 Vol.5 No.2

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.

다시 보는 알츠하이머병의 아밀로이드 가설

김병수(Byung Soo Kim) 대한생물치료정신의학회 2014 생물치료정신의학 Vol.20 No.3

Alzheimer’s disease(AD) is one of the most common causes of degenerative dementia in the elderly, and is characterized by a progressive deterioration of memory and other higher cognitive functions. Amyloid plaque is observed in the brains of patients with AD and has received attention as a pathognomonic feature since the disease was first reported. The amyloid hypothesis proposes that the toxic accumulation of amyloid-β protein plays a dominant role in the development and progression of AD. Since this theory was first presented in the early 1990s, it has influenced the development of biomarkers for the earlier detection of AD and research to find new treatments. However, recent reports have shown that amyloid deposits are commonly observed in cognitively normal aged persons, and therapeutic agents that effectively reduce the concentration of amyloid-beta in the brains of AD patients have not been effective at improving either cognitive function or the activities of daily living. This suggests that we need to consider alternative theories for AD other than the amyloid hypothesis. This review focuses on the amyloid hypothesis, with details on the production, metabolism, and clearance of amyloid-beta, and on recent advances in the development of therapeutic agents based on this hypothesis.

A novel BACE inhibitor isolated from Eisenia bicyclis exhibits neuroprotective activity against β-amyloid toxicity

Lee, Jung Kwon,Byun, Hee-Guk The Korean Society of Fisheries and Aquatic Scienc 2018 Fisheries and Aquatic Sciences Vol.21 No.12

Alzheimer's disease (AD) is a disturbing and advanced neurodegenerative disease and is characterized pathologically by the accumulation of amyloid beta ($A{\beta}$) and the hyperphosphorylation of tau proteins in the brain. The deposition of $A{\beta}$ aggregates triggers synaptic dysfunction, and neurodegeneration, which lead to cognitive disorders. Here, we found that FF isolated from an eatable perennial brown seaweed E.bicyclis protect against $A{\beta}$-induced neurotoxicity in neuroblastoma cells stably transfected with two amyloid precursor protein (APP) constructs: the APP695 cDNA (SH-SY5Y-APP695swe). The FF demonstrated strong inhibitory activity for ${\beta}$-secretase ($IC_{50}$ $16.1{\mu}M$) and its inhibition pattern was investigated using Lineweaver-Burk and Dixon plots, and found to be non-competitive. Then, we tested whether FF could inhibit production of $A{\beta}$ in SH-SY5Y-APP695swe. FF inhibited the production of $A{\beta}$ and soluble-APP, residue of APP from cleaved APP by ${\beta}$-secretase. Our data show that FF can inhibit the production of $A{\beta}$ and soluble-$APP{\beta}$ via inhibition of ${\beta}$-secretase activity. Taken together these results suggest that FF may be worthy of future study as an anti-AD treatment.

ALS-linked mutant SOD1 proteins promote Aβ aggregates in ALS through direct interaction with Aβ

Jang, Ja-Young,Cho, Hyungmin,Park, Hye-Yoon,Rhim, Hyangshuk,Kang, Seongman Academic Press 2017 Biochemical and biophysical research communication Vol. No.

<P><B>Abstract</B></P> <P>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motor neurons. Aggregation of ALS-linked mutant Cu/Zn superoxide dismutase (SOD1) is a hallmark of a subset of familial ALS (fALS). Recently, intracellular amyloid-β (Aβ) is detected in motor neurons of both sporadic and familial ALS. We have previously shown that intracellular Aβ specifically interacts with G93A, an ALS-linked SOD1 mutant. However, little is known about the pathological and biological effect of this interaction in neurons. In this study, we have demonstrated that the Aβ-binding region is exposed on the SOD1 surface through the conformational changes due to misfolding of SOD1. Interestingly, we found that the intracellular aggregation of Aβ is enhanced through the direct interaction of Aβ with the Aβ-binding region exposed to misfolded SOD1. Ultimately, increased Aβ aggregation by this interaction promotes neuronal cell death. Consistent with this result, Aβ aggregates was three-fold higher in the brains of G93A transgenic mice than those of non Tg. Our study provides the first direct evidence that Aβ, an AD-linked factor, is associated to the pathogenesis of ALS and provides molecular clues to understand common aggregation mechanisms in the pathogenesis of neurodegenerative diseases. Furthermore, it will provide new insights into the development of therapeutic approaches for ALS.</P> <P><B>Highlights</B></P> <P> <UL> <LI> ALS-linked mutant SOD1 proteins directly interact with Aβ. </LI> <LI> Conformational change of misfolded SOD1 induces exposure of specific β-strand as an Aβ-binding region. </LI> <LI> Interaction with misfolded SOD1 and Aβ promotes Aβ aggregation and neuronal cell death. </LI> <LI> Pathological relevance of the interaction of Aβ and G93A for ALS: Misfolded SOD1 enhances Aβ aggregates in the brain of ALS transgenic mice. </LI> </UL> </P>