Actin dynamics and cofilin-actin rods in alzheimer disease.
Actin dynamics and cofilin-actin rods in alzheimer disease.
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DOI：
10.1002/cm.21282
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Bernstein BW
中科院分区：
文献类型：
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作者：
Bamburg JR;Bernstein BW
细胞骨架异常和突触丢失是家族性和散发性阿尔茨海默病（AD）的典型特征，由多种应激（如神经炎症、氧化应激和能量应激）诱导，每种应激均可由促炎细胞因子或淀粉样蛋白-β（Aβ）肽引发或增强。细胞外含Aβ的斑块和细胞内含磷酸化tau的神经原纤维缠结是确诊AD所需的死后病理学，并且一直是大多数研究的焦点。然而，AD脑，而不是正常脑，也具有由ADF/cofilin-肌动蛋白以1：1复合物（杆）组成的细胞质杆状丝束的增加的水平。Cofilin是哺乳动物神经元中主要的ADF/cofilin亚型，在低Cofilin/肌动蛋白比率下切断肌动蛋白丝，在高Cofilin/肌动蛋白比率下稳定肌动蛋白丝。它与F-肌动蛋白中的ADP-肌动蛋白亚基协同结合。Cofilin通过去磷酸化而被激活，并且可以在应激神经元中被氧化以形成二硫键连接的二聚体，这是将Cofilin-肌动蛋白丝捆绑成稳定的杆所需的。在神经突内形成的杆状物通过隔离丝切蛋白、破坏正常肌动蛋白动力学、阻断转运和加剧线粒体膜电位损失而引起突触功能障碍。Aβ和促炎细胞因子通过细胞朊病毒蛋白依赖性激活NADPH氧化酶和产生活性氧来诱导视杆细胞。在这里，我们回顾了最近的进展，我们的理解cofilin的生物化学，杆的形成，和认知缺陷的发展。然后，我们将讨论杆形成突触损失的分子途径，可能是所有三个突出的当前AD假说之间的共同点，从而使杆有吸引力的治疗目标。
Cytoskeletal abnormalities and synaptic loss, typical of both familial and sporadic Alzheimer disease (AD), are induced by diverse stresses such as neuroinflammation, oxidative stress, and energetic stress, each of which may be initiated or enhanced by proinflammatory cytokines or amyloid-β (Aβ) peptides. Extracellular Aβ-containing plaques and intracellular phospho-tau-containing neurofibrillary tangles are postmortem pathologies required to confirm AD and have been the focus of most studies. However, AD brain, but not normal brain, also have increased levels of cytoplasmic rod-shaped bundles of filaments composed of ADF/cofilin-actin in a 1:1 complex (rods). Cofilin, the major ADF/cofilin isoform in mammalian neurons, severs actin filaments at low cofilin/actin ratios and stabilizes filaments at high cofilin/actin ratios. It binds cooperatively to ADP-actin subunits in F-actin. Cofilin is activated by dephosphorylation and may be oxidized in stressed neurons to form disulfide-linked dimers, required for bundling cofilin-actin filaments into stable rods. Rods form within neurites causing synaptic dysfunction by sequestering cofilin, disrupting normal actin dynamics, blocking transport, and exacerbating mitochondrial membrane potential loss. Aβ and proinflammatory cytokines induce rods through a cellular prion protein-dependent activation of NADPH oxidase and production of reactive oxygen species. Here we review recent advances in our understanding of cofilin biochemistry, rod formation, and the development of cognitive deficits. We will then discuss rod formation as a molecular pathway for synapse loss that may be common between all three prominent current AD hypotheses, thus making rods an attractive therapeutic target.