Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression.
Marked calpastatin (CAST) depletion in Alzheimer's disease accelerates cytoskeleton disruption and neurodegeneration: neuroprotection by CAST overexpression.
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DOI：
10.1523/jneurosci.4119-08.2008
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发表时间：
2008-11-19
期刊：
影响因子：
--
通讯作者：
Nixon RA
中科院分区：
文献类型：
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作者：
Rao MV;Mohan PS;Peterhoff CM;Yang DS;Schmidt SD;Stavrides PH;Campbell J;Chen Y;Jiang Y;Paskevich PA;Cataldo AM;Haroutunian V;Nixon RA
钙蛋白酶活性增加与阿尔茨海默病(AD)的突触功能障碍和神经退行性变有关。阿尔茨海默病中钙蛋白酶活性增加的分子机制尚不清楚。在这里，我们证明了疾病的进展是由内源性钙蛋白酶抑制物Calastatin(CAST)从AD神经元中显著耗尽所推动的，该抑制物是由caspase-1、caspase-3和calain介导的。最初沿着树突的CAST枯竭在地形图上与Calain II和ERK 1/2激活、caspase-3切割tau以及tau和神经丝过度磷酸化相一致。这些相同的变化，连同细胞骨架蛋白分解和神经细胞死亡，伴随着海马区注射海人藻氨酸后的CAST耗竭，并且在过度表达人CAST的小鼠中显著减少。此外，在正常表达CAST的细胞中，通过shRNA减少CAST可在钙诱导的损伤水平上导致Calain介导的死亡，这对正常表达CAST的细胞是亚致命的。我们的结果有力地支持了一种新的假说，即多种异常激活的蛋白水解酶导致的CAST耗竭加速了阿尔茨海默病患者钙蛋白的失调，导致细胞骨架的破坏和神经退行性变。因此，模拟管型可能对AD具有神经保护作用。
Increased activity of calpains is implicated in synaptic dysfunction and neurodegeneration in Alzheimer’s disease (AD). The molecular mechanisms responsible for increased calpain activity in AD are not known. Here, we demonstrate that disease progression is propelled by a marked depletion of the endogenous calpain inhibitor, calpastatin (CAST), from AD neurons, which is mediated by caspase-1, caspase-3, and calpains. Initial CAST depletion focally along dendrites coincides topographically with calpain II and ERK 1/2 activation, tau cleavage by caspase-3, and tau and neurofilament hyperphosphorylation. These same changes, together with cytoskeletal proteolysis and neuronal cell death, accompany CAST depletion after intrahippocampal kainic acid administration to mice, and are substantially reduced in mice overexpressing human CAST. Moreover, CAST reduction by shRNA in neuronal cells causes calpain-mediated death at levels of calcium-induced injury that are sublethal to cells normally expressing CAST. Our results strongly support a novel hypothesis that CAST depletion by multiple abnormally activated proteases accelerates calpain dysregulation in AD leading to cytoskeleton disruption and neurodegeneration. CAST mimetics may, therefore, be neuroprotective in AD.