Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance

Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review, we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt, Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD. Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006     

南亚寡鬃实蝇的风险分析

本文根据国际粮农组织(FAO)风险分析的准则(IPPC),通过地理评估和管理标准、定殖及定殖后扩散的可能性、传入的可能性,危害性和防治的难度对对南瓜实蝇传入我国的风险进行,为制定我国针对性检疫措施提供资料依据。     

Overinhibition of Mitogen-Activated Protein Kinase Inducing Tau Hyperphosphorylation

To reveal the relationship between mitogen-activated protein kinase (MAPK) and tau phosphorylation, we used different concentration of PD98059, an inhibitor of MEK (MAPK kinase), to treat mice neuroblastma (N2a) cell line for 6 h. It showed that the activity of MAPK decreased in a dose-dependent manner. But Western blot and immunofluorescence revealed that just when the cells were treated with 16μmol/L PD98059, tau was hyperphosphorylated at Ser396/404 and Ser199/202 sites. We obtained the conclusion that overinhibited MAPK induced tau hyperphosphorylation at Ser396/404 and Ser199/202 sites.     

动态散射光信号的高速采集的实现

根据动态光散射原理中散射光信号涨落求取纳米级颗粒粒径的方法,介绍了应用TDS5052B数字示波器构建的高速信号采集实验装置,分别阐述了应用LabVIEW虚拟仪器软件设计的基于多倍延迟时间的高速的散射光子信号的采集、甄别与计数程序.实现了单通道的32 ms内散射光子信号采集,并得到了合理的实验结果.     

Developing pharmacological therapies for Alzheimer disease

Alzheimer disease (AD), while chronic and progressive with an average progression of 7 – 10 years, is both multifactorial and heterogeneous. Thus, AD offers a large window of opportunity and a large number of therapeutic targets to inhibit it. The selection of a therapeutic target, however, is one of the biggest challenges in developing a pharmacological treatment of this multifactorial disease. Inhibition of a pivotal downstream event is likely to benefit more patients than inhibition of an upstream event in AD pathogenesis. Neurofibrillary degeneration of abnormally hyperphosphorylated tau offers such a pivotal therapeutic target. Abnormal hyperphosphorylation of tau and not its aggregation into filaments appears to be the most deleterious step in neurofibrillary degeneration. Tau can be abnormally hyperphosphorylated by downregulation of protein phosphatase-2A activity or by upregulation of more than one tau kinase. Restoration of the phosphatase activity which is downregulated in AD brain or inhibition of GSK-3β and cdk5, which are required for AD-type abnormal hyperphosphorylation of tau, are among the most promising therapeutic strategies.     

维生素E对CA诱导的tau蛋白过度磷酸化的保护

通过免疫印迹,酶活性测定等方法在脑片水平研究维生素E(VE)对花萼海绵诱癌素(cA)诱导的骨架蛋白tau过度磷酸化的保护作用及机制．结果显示：01tmol／LCA使tau蛋白在Ser396／404,Serl98／199／202位点的磷酸化程度显著升高,丙二醛(MDA)含量及超氧化物歧化酶(s0D)活性显著升高;VE能使tau蛋白上述位点的磷酸化水平显著降低,同时降低CA诱导的vH)A含量的升高及进一步升高SK)D的活性．提示CA不仅能够在脑片水平诱导tau的过度磷酸化,同时诱导氧化应激反应;vE对CA诱导的氧化应激反应及tau蛋白过度磷酸化具有保护作用．     

OA诱导大鼠基底核Ach降低及τ蛋白过度磷酸化

研究了磷酸酯酶(proteinphosphatase,PP)对胆碱能神经元功能的影响,将PP抑制剂岗田酸(okadaic acid,OA)注入大鼠双侧Meynert基底核,并经免疫印迹检测r(tau)蛋白磷酸化程度、经微渗透结合HL,PC检测Ach、经Morris水迷宫检测大鼠的空间记忆能力,结果发现,Meynert基底核注射OA后,Ach水平降低,τ蛋白在Sei-198／Sei-199／Set-202,Ser-396／Ser-404位点发生过度磷酸化,并伴有大鼠空间记忆障碍,本研究结果提示PP活性降低可能参与了神经元纤维缠结形成、胆碱能神经元功能及认知功能障碍,在AD发病机制中起重要作用。     

Causes of oxidative stress in Alzheimer disease

Oxidative stress is one of the earliest events of Alzheimer disease (AD), with implications as an important mediator in the onset, progression and pathogenesis of the disease. The generation of reactive oxygen species (ROS) and its consequent cellular damage/response contributes to much of the hallmark AD pathology seen in susceptible neurons. The sources of ROS-mediated damage appear to be multi-faceted in AD, with interactions between abnormal mitochondria, redox transition metals, and other factors. In this review, we provide an overview of these potential causes of oxidative stress in AD.     

Alzheimer's disease: fundamental and therapeutic aspects

Alzheimer's disease is the most common type of progressive and debilitating dementia affecting aged people. In some early — as well as late-onset familial cases, a genetic linkage with chromosomes 14, 21 (early-onset) or 19 (late-onset) has been indicated. Furthermore, a direct or indirect role has been attributed to normal or structurally altered amyloid -protein (concentrated in senile plaques) and/or excessively phosphorylated tau protein (located in neurofibrillary tangles). Degeneration of cholinergic neurons and concomitant impairment of cortical and hippocampal neurotransmission lead to cognitive and memory deficits. Several compounds are being tested in attempts to prevent and/or cure Alzheimer's disease, including tacrine, which has very modest efficacy in a sub-group of patients, and new acetylcholinesterase inhibitors. Pilot experiments have also been launched using nerve growth factor (NGF) to prevent or stabilize the processes of cholinergic pathway degeneration. Alternatively, antioxidants, free radical scavengers and/or non steroidal anti-inflammatory agents may be screened as potential therapies for neurodegenerative diseases induced by multiple endogenous and/or exogenous factors. The recent use of transgenic mice, in parallel with other genetic, biochemical and neurobiological systems, in vivo and/or in vitro (cell cultures), should accelerate the discovery and development of specific drugs for the treatment of Alzheimer's disease.     

光温湿因子对三种果实蝇种群生殖力影响的比较研究

本文研究（ａ）稳定的温度和相对湿度（２５℃，ＲＨ７５％～９５％），不同光周期（Ｌ：Ｄ＝８：１８～１６：８）的条件和（ｂ）周期性变化的温度、相对湿度和不同光周期下（２０～２５℃，ＲＨ７５％～７５％，Ｌ：Ｄ＝１０：１４；２５～３２℃，ＲＨ７５％～９５％，Ｌ：Ｄ＝１４：１０）对瓜实蝇Ｂａｃｔｒｏｃｅｒａｃｕｃｕｒｂｉｔａｅ南瓜实蝇Ｂ．ｔａｕ和桔小实蝇Ｂ．ｄｏｒｓａｌｉｓ种群生殖力的影响，结果表明，中长期光照对三种实蝇的种群增殖稍为有利，短光周期对南瓜实蝇种群的增殖不利。不论是在稳定的温度和相对湿度，不同光周期条件下，或在周期性变化的温度和相对湿度，稳定的光周期条件下，３种实蝇的生殖期长，产卵量大，世代重迭，而桔小实蝇和南瓜实蝇的产卵较集中，在２０～２５℃周期性变动的条件下，５０％Σｌ＿ｘｍ＿ｘ在成虫开始产卵后６饲左右，瓜实蝇则要１３０～１４０ｄ；在２５～３２℃，桔小实蝇和南瓜实蝇的５０％Σｌ＿ｘｍ＿ｘ为４０ｄ，而瓜实蝇要７０ｄ，桔小实蝇和南瓜实蝇的种群增殖速度快，种群在短时间内能迅速形成增殖高峰，是典型的ｒ生态对策，瓜实蝇的产卵前期较长，产卵期长，卵几乎均匀分布于产卵过程，属于偏ｒ生态对策。