Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery.
Selecting for neurogenic potential as an alternative for Alzheimer's disease drug discovery.
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DOI：
10.1016/j.jalz.2016.03.016
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Schubert D
中科院分区：
文献类型：
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作者：
Prior M;Goldberg J;Chiruta C;Farrokhi C;Kopynets M;Roberts AJ;Schubert D
阿尔茨海默病（AD）的神经元死亡，不能有效地替代。维持神经细胞数量的另一种方法是鉴定刺激老年人内源性神经干细胞增殖的化合物，以取代失去的神经元。然而，除非神经源性药物也具有神经保护作用，否则替换丢失的神经元将不足以阻止疾病进展。神经保护AD候选药物J147被证明可以增强记忆，改善树突结构，并刺激老年小鼠大脑生发区域的细胞分裂。基于J147的潜在神经发生潜力，我们开发了一种神经干细胞筛选实验来优化J147的人类神经发生衍生物。J147的最佳衍生物CAD-031保持了J147的神经保护和记忆增强特性，但在人神经干细胞实验中表现出更强的活性。在治疗与年龄相关的神经退行性疾病时，单一药物的神经保护、神经发生和记忆增强的综合特性比任何单独的活动都更有效。
Neurons die in Alzheimer’s disease (AD) and are not effectively replaced. An alternative approach to maintain nerve cell number is to identify compounds that stimulate the proliferation of endogenous neural stem cells in old individuals to replace lost neurons. However, unless a neurogenic drug is also neuroprotective, the replacement of lost neurons will not be sufficient to stop disease progression. The neuroprotective AD drug candidate J147 is shown to enhance memory, improve dendritic structure, and stimulate cell division in germinal regions of the brains of very old mice. Based upon the potential neurogenic potential of J147, a neuronal stem cell screening assay was developed to optimize derivatives of J147 for human neurogenesis. The best derivative of J147, CAD-031, maintains the neuroprotective and memory enhancing properties of J147, yet is more active in the human neural stem cell assays. The combined properties of neuroprotection, neurogenesis and memory enhancement in a single drug are more likely to be effective for the treatment of age-associated neurodegenerative disorders than any individual activity alone.