Novel Detox Gel Depot sequesters β-Amyloid Peptides in a mouse model of Alzheimer's Disease.
Novel Detox Gel Depot sequesters β-Amyloid Peptides in a mouse model of Alzheimer's Disease.
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新颖的 Detox Gel Depot 在阿尔茨海默病小鼠模型中隔离 β-淀粉样肽。
DOI：
10.1007/s10989-011-9283-7
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发表时间：
2012
影响因子：
2.5
通讯作者：
Sundaram,Pazhani
中科院分区：
文献类型：
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作者：
Sundaram,RanjiniK;Kasinathan,Chinnaswamy;Stein,Stanley;Sundaram,Pazhani
阿尔茨海默病 (AD) 是一种使人衰弱的神经退行性疾病，是由 39-43 个氨基酸肽（β 淀粉样蛋白或 Aβ）在脑实质和脑血管系统中聚集和积累引起的。合理的方法是使用干扰 Aβ-Aβ 相互作用并破坏聚合的药物。能够与 Aβ 分子中的 KLVFF（氨基酸 16-20）区域结合的肽配体已作为可能的候选药物进行了研究。这种五肽的逆反 (RI) 肽 ffvlk 已被证明能够以中等亲和力结合由 Aβ 制成的人工原纤维。我们假设，通过将四聚体 RI 肽ffvlk 与聚乙二醇聚合物链共价连接而合成的“排毒凝胶”将像“水槽”一样，从周围环境中捕获 Aβ 肽。我们之前证明了这一假设在体外系统中有效。本研究将这一假设扩展到 AD 小鼠体内模型，并确定了我们的排毒凝胶的治疗效果。我们向 AD 模型小鼠皮下注射排毒凝胶，并分析 Aβ-42 的大脑水平和记忆参数的改善。结果显示，排毒凝胶治疗小鼠的大脑淀粉样蛋白负荷减少。接受治疗的小鼠的记忆参数有所改善。没有观察到不良的免疫反应。数据强烈表明我们的排毒凝胶可用作消耗大脑 Aβ 水平的有效疗法。考虑到最近放弃了失败的基于抗体的疗法，我们的排毒凝胶似乎具有作为非免疫疗法的优势。
Alzheimer’s disease (AD), a debilitating neurodegenerative disease is caused by aggregation and accumulation of a 39–43 amino acid peptide (amyloid β or Aβ) in brain parenchyma and cerebrovasculature. The rational approach would be to use drugs that interfere with Aβ–Aβ interaction and disrupt polymerization. Peptide ligands capable of binding to the KLVFF (amino acids 16–20) region in the Aβ molecule have been investigated as possible drug candidates. Retro-inverso (RI) peptide of this pentapeptide,ffvlk, has been shown to bind artificial fibrils made from Aβ with moderate affinity. We hypothesized that a ‘detox gel’, which is synthesized by covalently linking a tetrameric version of RI peptideffvlkto poly(ethylene glycol) polymer chains will act like a ‘sink’ to capture Aβ peptides from the surrounding environment. We previously demonstrated that this hypothesis works in an in vitro system. The present study extended this hypothesis to an in vivo mouse model of AD and determined the therapeutic effect of our detox gel. We injected detox gel subcutaneously to AD model mice and analyzed brain levels of Aβ-42 and improvement in memory parameters. The results showed a reduction of brain amyloid burden in detox gel treated mice. Memory parameters in the treated mice improved. No undesirable immune response was observed. The data strongly suggest that our detox gel can be used as an effective therapy to deplete brain Aβ levels. Considering recent abandonment of failed antibody based therapies, our detox gel appears to have the advantage of being a non-immune based therapy.