Several plant-derived compounds have demonstrated efficacy in pre-clinical Alzheimer's disease (AD) rodent models. Each of these compounds share a gallic acid (GA) moiety, and initial assays on this isolated molecule indicated that it might be responsible for the therapeutic benefits observed. To test this hypothesis in a more physiologically relevant setting, we investigated the effect of GA in the mutant human amyloid β-protein precursor/presenilin 1 (APP/PS1) transgenic AD mouse model. Beginning at 12 months, we orally administered GA (20 mg/kg) or vehicle once daily for 6 months to APP/PS1 mice that have accelerated Alzheimer-like pathology. At 18 months of age, GA therapy reversed impaired learning and memory as compared with vehicle, and did not alter behavior in nontransgenic littermates. GA-treated APP/PS1 mice had mitigated cerebral amyloidosis, including brain parenchymal and cerebral vascular β-amyloid deposits, and decreased cerebral amyloid β-proteins. Beneficial effects co-occurred with reduced amyloidogenic and elevated nonamyloidogenic APP processing. Furthermore, brain inflammation, gliosis, and oxidative stress were alleviated. We show that GA simultaneously elevates α- and reduces β-secretase activity, inhibits neuroinflammation, and stabilizes brain oxidative stress in a pre-clinical mouse model of AD. We further demonstrate that GA increases abundance of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10, Adam10) proprotein convertase furin and activates ADAM10, directly inhibits β-site APP cleaving enzyme 1 (BACE1, Bace1) activity but does not alter Adam10 or Bace1 transcription. Thus, our data reveal novel post-translational mechanisms for GA. We suggest further examination of GA supplementation in humans will shed light on the exciting therapeutic potential of this molecule.

中文翻译：

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没食子酸是一种双重 α/β-分泌酶调节剂，可逆转阿尔茨海默病小鼠的认知障碍和修复病理。

几种植物来源的化合物已在临床前阿尔茨海默病 (AD) 啮齿动物模型中证明有效。这些化合物中的每一种都共享一个没食子酸 (GA) 部分，对这种分离分子的初步分析表明，它可能是观察到的治疗益处的原因。为了在更具生理学相关性的环境中检验这一假设，我们研究了 GA 在突变的人类淀粉样蛋白 β 蛋白前体/早老素 1 (APP/PS1) 转基因 AD 小鼠模型中的作用。从 12 个月开始，我们每天一次向 APP/PS1 小鼠口服 GA（20 毫克/千克）或赋形剂，持续 6 个月，这些小鼠已经加速了阿尔茨海默病样病理。在 18 个月大时，与载体相比，GA 疗法逆转了受损的学习和记忆，并且没有改变非转基因同窝仔的行为。GA 处理的 APP/PS1 小鼠减轻了脑淀粉样变性，包括脑实质和脑血管 β-淀粉样蛋白沉积，并减少了脑淀粉样蛋白 β-蛋白。有益作用与减少的淀粉样蛋白生成和非淀粉样蛋白生成的 APP 处理同时发生。此外，大脑炎症、神经胶质增生和氧化应激得到缓解。我们表明，在 AD 的临床前小鼠模型中，GA 同时提高 α- 和降低 β-分泌酶活性，抑制神经炎症，并稳定脑氧化应激。我们进一步证明 GA 增加了含有解整合素和金属蛋白酶结构域的蛋白 10（ADAM10，Adam10）前蛋白转化酶弗林蛋白酶的丰度并激活 ADAM10，直接抑制 β 位点 APP 裂解酶 1（BACE1，Bace1）活性但不改变 Adam10 或Bace1 转录。因此，我们的数据揭示了 GA 的新翻译后机制。我们建议进一步检查人体中的 GA 补充剂将揭示该分子令人兴奋的治疗潜力。