Discovery of a Novel Pharmacological and Structural Class of Gamma Secretase Modulators Derived from the Extract of Actaea racemosa

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A novel method for the rapid determination of beta-amyloid toxicity on acute hippocampal slices using MTT and LDH assays

It is difficult task to measure precisely the toxic effect of beta-amyloid (Aβ 1-42) peptides and also the protective effect of novel drug candidates against Aβ-peptides. The widely used MTT-assay in cell lines or primary cell cultures could be insensitive against Aβ-peptides. We describe here an easy and relevant method for testing Aβ 1-42 toxicity on acute hippocampal slices derived from rat. Brain slice viability in different conditions was measured using MTT and LDH assays. The concomitant use of these two assays can give detailed and relevant results on the toxic effect of Aβ 1-42 in oxygen-glucose deprived (OGD) acute brain slice model. Both assays are capable of quantifying tissue viability by measuring optical density (OD). We found that simultaneous application of OGD and Aβ 1-42 treatment induced a more intensive decrease in hippocampal slice viability than their separate effects. The use of MTT and LDH assay for quantifying brain slice viability proved to be an easy ex vivo method for investigating Aβ toxicity. Testing brain slices is more relevant in Alzheimer's Disease research than using in vitro cell cultures, due to maintenance of the three dimensional cellular network, the cell variability and intact cell connections.     

阿尔茨海默病与血管性痴呆的18F-FDDNP脑PET显像

目的探讨1-{6-[（2-^18F-氟乙基）-甲氨基]-2-萘基}-亚乙基丙二氰（^18F-FDDNP）PET脑显像鉴别诊断阿尔茨海默病（AD）与血管性痴呆（VaD）的价值。方法分别对9例AD、6例VaD及6例智能正常老年对照者（NC）进行^18F-FDDNPPET脑显像，受试者分别在药物注射后5、25、45min采集图像。结果AD患者大脑皮层及皮层下灰质核团3个时间段放射性清除情况与其他2组图像有明显的不同。药物注射5-45min后脑内放射性清除率：AD组（39％～45％），较NC组（55％～64％）明显减低（P〈0．05）。除外基底节区，VaD组（47％～59％）与NC组比较无显著性差异（P〉0．05）。结论^18F-FDDNPPET脑显像在AD诊断及与VaD的鉴别诊断中有重要的临床应用价值。     

Chronic Stress and Alzheimer��s Disease-Like Pathogenesis in a Rat Model: Prevention by Nicotine

Environmental factors including chronic stress may play a critical role in the manifestation of Alzheimer’s disease (AD).This review summarizes our studies of the aggravation of the impaired cognitive ability and its cellular and molecular correlates by chronic psychosocial stress and prevention by nicotine in an Aβ rat model of AD. We utilized three approaches: learning and memory tests in the radial arm water maze, electrophysiological recordings of the cellular correlates of memory, long-term potentiation (LTP) and long-term depression (LTD), in anesthetized rats, and immunoblot analysis of synaptic plasticity- and cognition-related signaling molecules. The Aβ rat model, representing the sporadic form of established AD, was induced by continuous i.c.v. infusion of a pathogenic dose of Aβ peptides via a 14- day osmotic pump. In this AD model, chronic stress intensified cognitive deficits, accentuated the disruption of signaling molecules levels and produced greater depression of LTP than what was seen with Aβ infusion alone. Chronic treatment with nicotine was highly efficient in preventing the effects of Aβ infusion and the exacerbating impact of chronic stress. Possible mechanisms for the effect of chronic stress are discussed.     

Dietary restriction delays aging, but not neuronal dysfunction, in Drosophila models of Alzheimer's disease

Dietary restriction (DR) extends lifespan in diverse organisms and, in animal and cellular models, can delay a range of aging-related diseases including Alzheimer's disease (AD). A better understanding of the mechanisms mediating these interactions, however, may reveal novel pathways involved in AD pathogenesis, and potential targets for disease-modifying treatments and biomarkers for disease progression. Drosophila models of AD have recently been developed and, due to their short lifespan and susceptibility to genetic manipulation, we have used the fly to investigate the molecular connections among diet, aging and AD pathology. DR extended lifespan in both Arctic mutant Aβ42 and WT 4R tau over-expressing flies, but the underlying molecular pathology was not altered and neuronal dysfunction was not prevented by dietary manipulation. Our data suggest that DR may alter aging through generalised mechanisms independent of the specific pathways underlying AD pathogenesis in the fly, and hence that lifespan-extending manipulations may have varying effects on aging and functional declines in aging-related diseases. Alternatively, our analysis of the specific effects of DR on neuronal toxicity downstream of Aβ and tau pathologies with negative results may simply confirm that the neuro-protective effects of DR are upstream of the initiating events involved in the pathogenesis of AD.     

Cyanidin suppresses amyloid beta-induced neurotoxicity by inhibiting reactive oxygen species-mediated DNA damage and apoptosis in PC12 cells

Amyloid beta(Aβ)-induced oxidative stress is a major pathologic hallmark of Alzheimer's disease. Cyanidin, a natural flavonoid compound, is neuroprotective against oxidative damage-mediated degeneration. However, its molecular mechanism remains unclear. Here, we investigated the effects of cyanidin pretreatment against Aβ-induced neurotoxicity in PC12 cells, and explored the underlying mechanisms. Cyanidin pretreatment significantly attenuated Aβ-induced cell mortality and morphological changes in PC12 cells. Mechanistically, cyanidin effectively blocked apoptosis induced by Aβ, by restoring the mitochondrial membrane potential via upregulation of Bcl-2 protein expression. Moreover, cyanidin markedly protected PC12 cells from Aβ-induced DNA damage by blocking reactive oxide species and superoxide accumulation. These results provide evidence that cyanidin suppresses Aβ-induced cytotoxicity, by preventing oxidative damage mediated by reactive oxide species, which in turn inhibits mitochondrial apoptosis. Our study demonstrates the therapeutic potential of cyanidin in the prevention of oxidative stress-mediated Aβ neurotoxicity.     

S14G-humanin restored cellular homeostasis disturbed by amyloid-beta protein

Humanin is a potential therapeutic agent for Alzheimer’s disease,and its derivative,S14G-humanin,is 1 000-fold stronger in its neuroprotective effect against Alzheimer’s disease-relevant insults.Although effective,the detailed molecular mechanism through which S14G-humanin exerts its effects remains unclear.Data from this study showed that fibrillar amyloid-beta 40 disturbed cellular homeostasis through the cell membrane,increasing intracellular calcium,generating reactive oxygen species,and decreasing the mitochondrial membrane potential.S14G-humanin restored these responses.The results suggested that S14G-humanin blocked the effects of amyloid-beta 40 on the neuronal cell membrane,and restored the disturbed cellular homeostasis,thereby exerting a neuroprotective effect on hippocampal neurons.     

Targeting Metal-Aβ Aggregates with Bifunctional Radioligand [11C]L2-b and a Fluorine-18 Analogue [18F]FL2-b

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Cellular Polyamines Promote Amyloid-Beta (Aβ) Peptide Fibrillation and Modulate the Aggregation Pathways

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