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.

Standardized Ginkgo biloba extract EGb 761 exhibits beneficial effects to patients with Alzheimer's disease (AD). It was previously demonstrated that EGb 761 inhibits amyloid beta (Abeta) oligomerization in vitro, protects neuronal cells against Abeta toxicity, and improves cognitive defects in a mouse model of AD (Tg 2576). In this study, the neurogenic potential of EGb 761 and its effect on cAMP response element binding protein (CREB) were examined in a double transgenic mouse model (TgAPP/PS1). EGb 761 significantly increases cell proliferation in the hippocampus of both young (6 months) and old (22 months) TgAPP/PS1 mice, and the total number of neuronal precursor cells in vitro in a dose-dependent manner. Furthermore, Abeta oligomers inhibit phosphorylation of CREB and cell proliferation in the hippocampus of TgAPP/PS1 mice. Administration of EGb 761 reduces Abeta oligomers and restores CREB phosphorylation in the hippocampus of these mice. The present findings suggest that 1) enhanced neurogenesis by EGb 761 may be mediated by activation of CREB, 2) stimulation of neurogenesis by EGb 761 may contribute to its beneficial effects in AD patients and improved cognitive functions in the mouse model of AD, and 3) EGb 761 has therapeutic potential for the prevention and improved treatment of AD.

Alzheimer's disease (AD) has been associated with aggregation of beta-amyloid peptide (Abeta) and cell death in the brain. Using various models, such as the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the mouse Mus musculus, investigators have attempted to imitate the pathology process of AD for better understanding of the cellular mechanisms and for possible therapeutic intervention. Among many in vitro and in vivo models of AD, transgenic C. elegans expressing human Abeta has shown its own advantages. The transgenic C. elegans model have been used in studying AD due to its short life span, facility to maintain, ability to develop muscle-associated deposits reactive to amyloid-specific dyes and the concomitant progressive paralysis phenotype. Moreover, the transgenic C. elegans exhibits increased levels of reactive oxygen species (ROS) and protein carbonyls, similar to those observed in AD patients, supporting the current theory on Abeta-induced oxidative stress and subsequent neurodegeneration in AD. DNA microarray assays of the worm demonstrated several stress-related genes being upregulated, particularly two genes homologous to human alphaB-crystallin and tumor necrosis factor-related protein, which were also upregulated in postmortem AD brain. Studies in our laboratory along with others suggest that the transgenic C. elegans model is a suitable in vivo model to relate Abeta-expression with its toxicity, which may underlie AD pathology. It may also be used as a tool for pharmacological evaluation of novel therapeutic agents.

Background: Epidemiological studies have associated estrogen replacement therapy with a lower risk of developing Alzheimer's disease, but a higher risk of developing breast cancer and certain cardiovascular disorders. The neuroprotective effect of estrogen prompted us to determine potential therapeutic impact of soy-derived estrogenic compounds. Transgenic C. elegans, that express human beta amyloid (Aβ), were fed with soy derived isoflavones genistein, daidzein and glycitein (100 µg/ml) and then examined for Aβ-induced paralysis and the levels of reactive oxygen species.

Geological observations reveal existence of a unique form of plate subduction featuring subduction on both sides of one single oceanic plate, which is termed divergent double subduction (DDS). DDS may play an important role in facilitating tectonic processes like closure of oceanic basins, accretion and amalgamation of magmatic arcs, and growth of continents. However, this type of subduction has been largely a conceptual model and the geodynamics behind DDS are still poorly constrained. The Molucca Sea subduction zone in SE Asia has been considered as a Cenozoic example of DDS based on geophysical and geological data and provides an opportunity for detailed assessment of how DDS occurs. Here we present 3‐D numerical modeling with aims to reproduce the geodynamic processes of DDS. Several factors that may have important influences on the evolution of DDS are evaluated, including the geometry of the subducting plate, the order of subduction initiation on both sides, the far‐field boundary conditions and thickness of the overriding plates, and the negative buoyancy of the subducting plate. Our results reproduce the observed asymmetrical shape of the subducting Molucca Sea plate and the bending of Halmahera and Sangihe arcs and suggest that DDS is possible if effective escape of the slab‐trapped upper mantle overcomes the space problem, otherwise the slab‐trapped mantle may hinder the sustainability of subduction. We therefore conclude that DDS is associated with closure of narrow and short oceanic plate, and large‐scale double subduction is rare in nature probably owing to space problem.

NCT01622140.

We recommend BRCA testing to all Chinese OC patients and those general Chinese who have family members with hereditary breast and ovarian related cancer (HBOC)-related cancers. Variants carriers would not only benefit from early prevention of OC but also for the medical management.

Heat shock response, mediated by heat shock proteins, is a highly conserved physiological process in multicellular organisms for reestablishment of cellular homeostasis. Expression of heat shock factors and subsequent heat shock protein plays a role in protection against proteotoxicity in invertebrate and vertebrate models. Proteotoxicity due to β-amyloid peptide (Aβ) oligomerization has been linked to the pathogenesis of Alzheimer's disease. Previously, we demonstrated that progressive paralysis induced by expression of human Aβ 1-42 in transgenic C. elegans was alleviated by Aβ oligomer inhibitors ginkgo biloba extract and its constituents (Wu, et al., J. Neurosci 2006, 26:13102-13). In this study, we apply a protective heat shock to the transgenic C. elegans and demonstrate: 1) a remarkable delay in paralysis, 2) increased expression of small heat shock protein HSP16.2, and 3) significant reduction of Aβ oligomers in a heat shock timedependent manner. These results suggest that transient heat shock lessens Aβ toxicity by diminishing Aβ oligomerization, which provide a link between up regulation of endogenous chaperone proteins and protection against Aβ proteotoxicity in vivo.