The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice.
The neurotrophic compound J147 reverses cognitive impairment in aged Alzheimer's disease mice.
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DOI：
10.1186/alzrt179
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Schubert D
中科院分区：
文献类型：
--
作者：
Prior M;Dargusch R;Ehren JL;Chiruta C;Schubert D
阿尔茨海默病（AD）是一种与年龄有关的致命神经退行性疾病，尽管经过多年的研究，目前还没有治疗这种疾病的药物。在AD啮齿动物模型中筛选潜在的治疗方法通常依赖于在病理出现之前测试化合物，从而模拟疾病预防而不是疾病改造。此外，这种筛选方法并不能反映AD患者的临床表现，这可以解释为什么在动物模型中鉴定为有益的化合物不能转化为临床试验中疾病修饰化合物。显然，需要一种更好的阿尔茨海默病临床前药物筛选方法。为了更准确地反映临床环境，我们使用了一种替代筛选策略，涉及在病理已经进展的疾病阶段对AD小鼠进行治疗。老年（20月龄）转基因AD小鼠（APP/swePS1ΔE9）被喂食一种特别有效、具有口服活性、增强记忆和神经营养的分子J147。采用认知行为、组织学、ELISA和Western blotting检测J147对大鼠记忆、淀粉样蛋白代谢和神经保护通路的影响。J147还在东莨菪碱诱导的C57Bl/6J小鼠记忆损伤模型中进行了研究，并与多奈哌齐进行了比较。还包括J147的药理学和安全性的详细信息。本文提供的数据表明，在疾病晚期给药时，J147具有挽救认知缺陷的能力。J147改善老年AD小鼠记忆的能力与其诱导神经生长因子NGF（神经生长因子）和脑源性神经营养因子BDNF（脑源性神经营养因子）以及几种对学习和记忆重要的BDNF反应蛋白有关。在东莨菪碱模型中，J147和多奈哌齐的比较表明，虽然这两种化合物在修复短期记忆方面具有可比性，但J147在修复空间记忆方面更优越，两者结合使用对上下文和线索记忆效果最好。J147是一种令人兴奋的新化合物，在动物研究中非常有效，安全且具有口服活性。J147是一种潜在的阿尔茨海默病治疗药物，因为它能够提供即时的认知益处，并且在这些研究中证明，它也有可能阻止甚至逆转有症状动物的疾病进展。
Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required. To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1ΔE9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included. Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory. J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies.
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