Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model.
Cyclophilin D deficiency improves mitochondrial function and learning/memory in aging Alzheimer disease mouse model.
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DOI：
10.1016/j.neurobiolaging.2009.03.003
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发表时间：
2011-03
影响因子：
4.2
通讯作者：
Yan S
中科院分区：
文献类型：
--
作者：
Du H;Guo L;Zhang W;Rydzewska M;Yan S
线粒体应激是阿尔茨海默病(AD)的早期特征之一。线粒体Aβ与线粒体毒性有关。我们最近的研究表明，亲环素D介导的线粒体通透性转换孔是A-β和氧化应激诱导神经元和突触应激的重要机制。在过量表达突变型淀粉样前体蛋白(APP)和Aβ(MAPP)的转基因AD小鼠中，CypD缺乏可改善线粒体和突触功能以及长达12个月的学习/记忆。在这里，我们提供了CypD缺乏对老年AD小鼠(22-24个月)的保护作用的证据。CypD缺陷的MAPP小鼠表现出较少的钙诱导的线粒体肿胀，增加了线粒体的钙摄取能力，保存了线粒体的呼吸功能，改善了空间学习/记忆，即使在老年(已知为晚期AD病理和突触功能障碍的年龄)。这些数据表明，在阿尔茨海默病小鼠模型中，取消CypD导致了对Aβ毒性的持续终身保护，从而表明阻断CypD可能有利于阿尔茨海默病的治疗。
Mitochondrial stress is one of the early features of Alzheimer disease (AD). Mitochondrial Aβ has been linked to mitochondrial toxicity. Our recent study demonstrated that cyclophilin D (CypD) mediated mitochondrial permeability transition pore (mPTP) is an important mechanism for neuronal and synaptic stress induced by both Aβ and oxidative stress. In transgenic AD-type mice overexpressing mutant amyloid precursor protein (APP) and Aβ (mAPP), CypD deficiency improves mitochondrial and synaptic function and learning/memory up to 12 months old. Here we provide evidence of the protective effects of CypD deficiency in aged AD mice (22–24 months). CypD deficient mAPP mice demonstrate less calcium-induced mitochondrial swelling, increased mitochondrial calcium uptake capacity, preserved mitochondrial respiratory function and improved spatial learning/memory even in old age (known to be the age for late stage AD pathology and synaptic dysfunction). These data demonstrate that abrogation of CypD results in persistent life-long protection against Aβ toxicity in an Alzheimer’s disease mouse model, thereby suggesting that blockade of CypD may be of benefit for Alzheimer disease treatment.
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