Buznikov Gennady A, Nikitina Lyudmila A, Bezuglov Vladimir V, Milosević Ivan, Lazarević Lidija, Rogac Ljubica, Ruzdijić Sabera, Slotkin Theodore A, Rakić Ljubisa M
N.K. Koltzov Institute of Developmental Biology, Moscow, Russia.
Brain Res Bull. 2008 Jan 31;75(1):94-100. doi: 10.1016/j.brainresbull.2007.07.026. Epub 2007 Aug 20.
Accumulation of beta-amyloid protein is an Alzheimer's disease hallmark but also may be mechanistically involved in neurodegeneration. One of its cleavage peptides, Abeta42, has been used to evaluate the mechanisms underlying amyloid-induced cytotoxicity and targeting of acetylcholine systems. We studied Sphaerechinus granularis sea urchin embryos which utilize acetylcholine and other neurotransmitters as morphogens. At a threshold concentration of 0.1 microM Abeta42, there was damage to the larval skeleton, accumulation of ectodermal cells in the blastocoele and underdevelopment of larval arms. Raising the Abeta42 concentration to 0.2-0.4 microM produced anomalies depending on the stage at which Abeta42 was introduced: at the first cleavage divisions, abnormalities appeared within 1-2 cell cycles; at the mid-blastula stage, the peak period of sensitivity to Abeta42, gastrulation was blocked; at later stages, there was progressive damage to the larval skeleton, digestive tract and larval spicules, as well as regression of larval arms. Each of these anomalies could be offset by the addition of lipid-permeable analogs of acetylcholine (arachidonoyl dimethylaminoethanol), serotonin (arachidonoyl serotonin) and cannabinoids (arachidonoyl vanillylamine), with the greatest activity exhibited by the acetylcholine analog. These results indicate that sea urchin embryos provide a model suitable to characterize the mechanisms underlying the cytotoxicity of Abeta42, as well as providing a system that enables the rapid screening of potential therapeutic interventions. The protection provided by neurotransmitter analogs, especially that for acetylcholine, points to unsuspected advantages of existing therapies that enhance cholinergic function, as well as indicating novel approaches that may prove protective in Alzheimer's disease.
β-淀粉样蛋白的积累是阿尔茨海默病的一个标志，但在神经退行性变的机制中也可能有涉及。其一种裂解肽β淀粉样蛋白42（Aβ42）已被用于评估淀粉样蛋白诱导细胞毒性及作用于乙酰胆碱系统的机制。我们研究了球形海胆（Sphaerechinus granularis）的胚胎，这些胚胎利用乙酰胆碱和其他神经递质作为形态发生素。在Aβ42阈值浓度为0.1微摩尔时，幼虫骨骼受损，外胚层细胞在囊胚腔中积聚，幼虫臂发育不全。将Aβ42浓度提高到0.2 - 0.4微摩尔会产生异常，这取决于引入Aβ42的阶段：在第一次卵裂时，1 - 2个细胞周期内就会出现异常；在囊胚中期，即对Aβ42敏感的高峰期，原肠胚形成受阻；在后期，幼虫骨骼、消化道和幼虫骨针会逐渐受损，幼虫臂也会退化。添加乙酰胆碱（花生四烯酰二甲基氨基乙醇）、5-羟色胺（花生四烯酰5-羟色胺）和大麻素（花生四烯酰香草胺）的脂质可渗透类似物可抵消上述每种异常，其中乙酰胆碱类似物表现出最大活性。这些结果表明，海胆胚胎提供了一个适合表征Aβ42细胞毒性机制的模型，同时也提供了一个能够快速筛选潜在治疗干预措施的系统。神经递质类似物提供的保护作用，尤其是对乙酰胆碱的保护作用，指出了增强胆碱能功能的现有疗法存在未被怀疑的优势，同时也表明了可能对阿尔茨海默病具有保护作用的新方法。
