Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.
Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer's disease.
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DOI：
10.1038/nm.1868
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发表时间：
2008-10
期刊：
影响因子：
82.9
通讯作者：
Du Yan, Shi
中科院分区：
文献类型：
--
作者：
Du, Heng;Guo, Lan;Fang, Fang;Chen, Doris;Sosunov, Alexander A.;McKhann, Guy M.;Yan, Yilin;Wang, Chunyu;Zhang, Hong;Molkentin, Jeffery D.;Gunn-Moore, Frank J.;Vonsattel, Jean Paul;Arancio, Ottavio;Chen, John Xi;Du Yan, Shi
亲环蛋白D （CypD，由Ppif编码）是线粒体通透性过渡孔的组成部分，其打开导致细胞死亡。本研究表明CypD与线粒体淀粉样蛋白β (Aβ)的相互作用增强了线粒体、神经元和突触的应激。cypd缺陷的皮质线粒体对Aβ-和Ca2+诱导的线粒体肿胀和通透性转变具有抗性。此外，它们具有更高的钙缓冲能力，产生更少的线粒体活性氧。此外，CypD的缺失可以保护神经元免受Aβ和氧化应激诱导的细胞死亡。值得注意的是，CypD缺乏显著改善了阿尔茨海默病小鼠模型的学习记忆和突触功能，并减轻了a β介导的长期增强减弱。因此，cypd介导的线粒体通透性过渡孔与阿尔茨海默病发病机制中观察到的细胞和突触扰动直接相关。阻断CypD可能是阿尔茨海默病的一种治疗策略。
Cyclophilin D (CypD, encoded by Ppif) is an integral part of the mitochondrial permeability transition pore, whose opening leads to cell death. Here we show that interaction of CypD with mitochondrial amyloid-β protein (Aβ) potentiates mitochondrial, neuronal and synaptic stress. The CypD-deficient cortical mitochondria are resistant to Aβ- and Ca2+-induced mitochondrial swelling and permeability transition. Additionally, they have an increased calcium buffering capacity and generate fewer mitochondrial reactive oxygen species. Furthermore, the absence of CypD protects neurons from Aβ- and oxidative stress-induced cell death. Notably, CypD deficiency substantially improves learning and memory and synaptic function in an Alzheimer's disease mouse model and alleviates Aβ-mediated reduction of long-term potentiation. Thus, the CypD-mediated mitochondrial permeability transition pore is directly linked to the cellular and synaptic perturbations observed in the pathogenesis of Alzheimer's disease. Blockade of CypD may be a therapeutic strategy in Alzheimer's disease.
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