Caspase-12 Activation is Involved in Amyloid-β Protein-Induced Synaptic Toxicity
Caspase-12 Activation is Involved in Amyloid-β Protein-Induced Synaptic Toxicity
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DOI：
10.3233/jad-2011-110326
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发表时间：
2011-01-01
影响因子：
4
通讯作者：
Arias, Clorinda
中科院分区：
文献类型：
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作者：
Quiroz-Baez, Ricardo;Ferrera, Patricia;Arias, Clorinda
突触丢失被认为是阿尔茨海默病(AD)认知损害的最佳相关性，越来越多的证据支持这样的观点，即在AD中引发神经元死亡的某些事件可以由突触室内caspase的局部激活启动。我们以前已经证明，突触前终末特别容易受到内质网(ER)应激的影响，这取决于淀粉样β蛋白(Aβ)。这种毒性包括肌动蛋白和突触素蛋白显着减少以及线粒体功能障碍。这种突触损伤可以通过与广泛的caspase抑制剂孵育来防止，这表明局部突触凋亡机制的激活。内质网驻留的caspase-12最初被确定为Aβ神经毒性的介体。因此，本研究旨在探讨在Aβ和ryanodine存在的情况下，caspase-12在大鼠皮层和海马区突触体内的存在和局部激活。在这种情况下，我们发现线粒体衰竭伴随着肌动蛋白水平的降低，这依赖于caspase-12的激活，这表明它参与了Aβ诱导的突触毒性。
Synapse loss is considered to be the best correlate of cognitive impairments in Alzheimer's disease (AD), and growing evidence supports the notion that certain events that trigger neuronal death in AD can be initiated by the local activation of caspases within the synaptic compartment. We have demonstrated previously that presynaptic terminals are particularly vulnerable to endoplasmic-reticulum (ER)-stress depending on amyloid-beta protein (A beta). This toxicity included a notable reduction of actin and synaptophysin protein and mitochondrial dysfunction. This synaptic damage was prevented by incubation with a wide range of caspase inhibitor, suggesting the activation of local synaptic apoptotic mechanisms. The ER-resident caspase-12 was initially identified as a mediator of A beta neurotoxicity. Thus, the current study was conducted to explore the presence and local activation of caspase-12 in cortical and hippocampal synaptosomes isolated from rat and from the triple transgenic mouse model of AD (3xTg-AD) in the presence of A beta and ryanodine. Under these conditions, we found mitochondrial failure accompanied by a reduction in actin levels which was dependent on caspase-12 activation suggesting its participation in A beta-induced synaptic toxicity.