CDGSH iron-sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid β (Aβ) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aβ-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

中文翻译：

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Cisd2的上调减弱了小鼠阿尔茨海默氏症相关的神经元丢失。

CDGSH含铁硫结构域的蛋白质2（Cisd2）是一种年龄依赖性下降的蛋白质，介导了哺乳动物的寿命。Cisd2缺乏症会导致衰老加速并缩短寿命，而Cisd2的持续表达可促进小鼠的寿命。阿尔茨海默氏病（AD）是老年性痴呆的最普遍形式，并且没有有效的治疗策略。我们使用AD小鼠模型研究了Cisd2上调是否能够改善淀粉样蛋白β（Aβ）毒性并防止神经元丢失。我们的研究取得了三个主要发现。首先，使用AD小鼠模型（APP / PS1双转基因小鼠），Cisd2的剂量似乎可以调节AD表型的严重性。Cisd2过表达（约2倍）可显着提高生存率并减轻与AD相关的病理缺陷。反过来，Cisd2缺乏症加速了AD的发病机理。其次，Cisd2过表达保护免受Aβ介导的线粒体损伤和神经元和神经元祖细胞损失的减弱。最后，Cisd2的增加将一组由AD失调的基因的表达谱向在野生型小鼠中观察到的模式转移。这些发现突出了基于Cisd2的疗法作为AD的潜在疾病缓解策略。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。Cisd2的增加使由AD失调的一组基因的表达谱向野生型小鼠中观察到的模式转移。这些发现突出了基于Cisd2的疗法作为AD的潜在疾病缓解策略。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。Cisd2的增加使由AD失调的一组基因的表达谱向野生型小鼠中观察到的模式转移。这些发现突出了基于Cisd2的疗法作为AD的潜在疾病缓解策略。©2019作者。John Wiley＆Sons Ltd代表大不列颠及爱尔兰病理学会出版的《病理学杂志》。