A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid‐β oligomeric complexes

Maezawa, Izumi; Hong, Hyun Seok; Wu, Ho Sheng; Battina, Srinivas K.; Rana, Sandeep; Iwamoto, Takeo; Radke, Gary A.; Pettersson, Erik; Martin, George M.; Hua, Duy H.; Jin, Lee‐Way

doi:10.1111/j.1471-4159.2006.03862.x

Cited by 80 publications

(135 citation statements)

References 48 publications

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“…The SPR protocol for the study of real-time direct binding of Ab and DBP was essentially similar to that described previously 47,48 and was performed using a Biacore X-100 (GE Healthcare). The CM5 sensor chip (GE Healthcare) was preactivated by a mixture of N-hydroxysuccinimide and N-ethyl-N'-(dimethylaminopropyl) carbodiimide.…”

Section: Methodsmentioning

confidence: 99%

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Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

et al. 2012

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The level of vitamin D-binding protein (DBP) is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD), suggesting a relationship with its pathogenesis. In this study, we investigated whether and how DBP is related to AD using several different approaches. A pull-down assay and a surface plasmon resonance binding assay indicated direct interactions between purified DBP and amyloid beta (Ab), which was confirmed in the brain of AD patients and transgenic AD model mice by immunoprecipitation assay and immunohistochemical double-staining method. Moreover, atomic force microscopic examination revealed that DBP reduced Ab aggregation in vitro. DBP also prevented Ab-mediated death in cultured mouse hippocampal HT22 cell line. Finally, DBP decreased Ab-induced synaptic loss in the hippocampus and rescued memory deficits in mice after injection of Ab into the lateral ventricle. These results provide converging evidence that DBP attenuates the harmful effects of Ab by a direct interaction, and suggest that DBP is a promising therapeutic agent for the treatment of AD.

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Section: Methodsmentioning

confidence: 99%

“…The resulting oligomers were examined by AFM (PARK Systems Inc., Suwon, South Korea) as described previously. 48 To estimate oligomer size using AFM, peptide solutions were aliquoted from reaction mixtures and immediately spotted onto freshly cleaved micas. The micas were then rinsed with water two times, and dried in air.…”

Section: Methodsmentioning

confidence: 99%

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

et al. 2012

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“…The evidence for or against these hypotheses is critical for specific therapeutic strategies. It has previously been demonstrated that small molecules inhibiting A␤ oligomers also reduced its toxicity (Walsh et al, 2005;Yang et al, 2005;Maezawa et al, 2006). However, most of these studies were conducted in vitro, and the use of a transgenic mice model of AD for pharmacological evaluation and mechanistic studies is time-consuming.…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Wu¹,

Wu²,

Butko³

et al. 2006

J. Neurosci.

378

366

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Amyloid-␤ (A␤) toxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration seen in Alzheimer's disease (AD). We previously demonstrated that the standardized Ginkgo biloba extract EGb 761, commonly used to enhance memory and by AD patients for dementia, inhibits A␤-induced apoptosis in neuroblastoma cells. In this study, we use EGb 761 and its single constituents to associate A␤ species with A␤-induced pathological behaviors in a model organism, Caenorhabditis elegans. We report that EGb 761 and one of its components, ginkgolide A, alleviates A␤-induced pathological behaviors, including paralysis, and reduces chemotaxis behavior and 5-HT hypersensitivity in a transgenic C. elegans. We also show that EGb 761 inhibits A␤ oligomerization and A␤ deposits in the worms. Moreover, reducing oxidative stress is not the mechanism by which EGb 761 and ginkgolide A suppress A␤-induced paralysis because the antioxidant L-ascorbic acid reduced intracellular levels of hydrogen peroxide to the same extent as EGb 761, but was not nearly as effective in suppressing paralysis in the transgenic C. elegans. These findings suggest that (1) EGb 761 suppresses A␤-related pathological behaviors, (2) the protection against A␤ toxicity by EGb 761 is mediated primarily by modulating A␤ oligomeric species, and (3) ginkgolide A has therapeutic potential for prevention and treatment of AD.

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“…Recent studies have shown that neurological dysfunction and neuronal toxicity are more prominently linked to particular forms of soluble Aβ oligomers (Podlisny et al, 1998;Walsh et al, 2002;Dahlgren et al, 2002;Chromy et al, 2003;Kayed et al, 2004;Lacor et al, 2004;Lesné et al, 2006). In addition, intraneuronal Aβ oligomers, identified by biochemical and immunohistochemical methods (Takahashi et al, 2004;Billings et al, 2005;Maezawa et al, 2006), appear to play an early pathological role in AD (Wirths et al, 2004). To minimize the degree of Aβ toxicity in the brain, small molecular weight compounds capable of inactivating or disaggregating existing neurotoxic oligomers of Aβ are particularly attractive therapeutic candidates (Blanchard et al, 2004;Yang et al, 2005;Walsh et al, 2005;Liu and Schubert, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…We therefore employ cell-based methods as the first line of screening, followed by cell-free methods for further characterization of compounds. Here we describe a combination of our previously published MC65 protection assay (Maezawa et al, 2006) and an assay modified from a sensitive MTT formazan exocytosis assay (MTT-FE) (Liu and Schubert, 2006) to efficiently select small molecule compounds that show promises in modifying the toxicity and/or structure of Aβ oligomers.…”

Section: Introductionmentioning

confidence: 99%

Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Aβ oligomer-induced cytotoxicity

et al. 2007

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The discovery of small molecule inhibitors of cytotoxicity induced by amyloid-β (Aβ) oligomers, either applied extracellularly or accumulated intraneuronally, is an important goal of drug development for Alzheimer's disease (AD), but has been limited by the lack of efficient screening methods. Here we describe our approach using two cell-based methods. The first method takes advantage of the unique ability of extracellularly applied Aβ oligomers to rapidly induce the exocytosis of formazan formed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We employed a short protocol to quantify this toxicity, and quickly identified two novel inhibitors, code-named CP2 and A5, from two compound libraries. A second independent screen of the same libraries using our previously published MC65 protection assay, which identifies inhibitors of toxicity related to intracellular Aβ oligomers, also selected the same two leads, suggesting that both assays select for the same anti-Aβ oligomer properties displayed by these compounds. We further demonstrated that A5 attenuated the progressive aggregation of existing Aβ oligomers, reduced the level of intracellular Aβ oligomers, and prevented the Aβ oligomer-induced death of primary cortical neurons, effects similar to those demonstrated by CP2. Our results suggest that, when combined, the two methods would generate fewer false results and give a high likelihood of identifying leads that show promises in ameliorating Aβ oligomer-induced toxicities within both intraneuronal and extracellular sites. Both assays are simple, suitable for rapid screening of a large number of medicinal libraries, and amenable for automation.

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A novel tricyclic pyrone compound ameliorates cell death associated with intracellular amyloid‐β oligomeric complexes

Cited by 80 publications

References 48 publications

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

Vitamin D-binding protein interacts with Aβ and suppresses Aβ-mediated pathology

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Combining the rapid MTT formazan exocytosis assay and the MC65 protection assay led to the discovery of carbazole analogs as small molecule inhibitors of Aβ oligomer-induced cytotoxicity

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