Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of Aβ in Alzheimer's disease.
Calpain cleavage and inactivation of the sodium calcium exchanger-3 occur downstream of Aβ in Alzheimer's disease.
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DOI：
10.1111/acel.12148
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发表时间：
2014-02
期刊：
影响因子：
7.8
通讯作者：
Noble W
中科院分区：
文献类型：
--
作者：
Atherton J;Kurbatskaya K;Bondulich M;Croft CL;Garwood CJ;Chhabra R;Wray S;Jeromin A;Hanger DP;Noble W
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是老年斑中β-淀粉样蛋白（a β）的病理沉积，细胞内神经原纤维缠结（nft）包括过度磷酸化的聚集tau，突触功能障碍和神经元死亡。大量证据表明，神经元钙稳态破坏是阿尔茨海默病的早期事件，可能介导突触功能障碍和神经元毒性。钠钙交换剂（NCXs）在调节细胞内钙的过程中发挥着重要作用，越来越多的数据表明，在这些交换剂发生异常的蛋白水解裂解后，NCX功能的降低可能导致神经退行性变。在这里，我们发现升高的calpain，而不是caspase-3，活性是AD大脑的一个显著特征。此外，我们观察到，相对于未受影响的组织和其他神经退行性疾病，AD脑组织中calpain介导的NCX3的切割增加，而相关家族成员NCX1的切割则没有增加。此外，NCX3蛋白水解程度与a - β1 - 42的含量显著相关。我们还发现，初级皮质神经元暴露于寡聚物Aβ1 - 42会导致NCX3的calpain依赖性裂解，并且NCX3功能的丧失与Aβ毒性有关。我们的研究结果表明，Aβ介导AD大脑中NCX3的钙蛋白酶裂解，因此NCX3活性的降低可能导致神经元内钙浓度的持续升高，这与AD中突触和神经元功能障碍有关。
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by pathological deposits of β-amyloid (Aβ) in senile plaques, intracellular neurofibrillary tangles (NFTs) comprising hyperphosphorylated aggregated tau, synaptic dysfunction and neuronal death. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium, and accumulating data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. Here, we show that elevated calpain, but not caspase-3, activity is a prominent feature of AD brain. In addition, we observe increased calpain-mediated cleavage of NCX3, but not a related family member NCX1, in AD brain relative to unaffected tissue and that from other neurodegenerative conditions. Moreover, the extent of NCX3 proteolysis correlated significantly with amounts of Aβ1–42. We also show that exposure of primary cortical neurons to oligomeric Aβ1–42 results in calpain-dependent cleavage of NCX3, and we demonstrate that loss of NCX3 function is associated with Aβ toxicity. Our findings suggest that Aβ mediates calpain cleavage of NCX3 in AD brain and therefore that reduced NCX3 activity could contribute to the sustained increases in intraneuronal calcium concentrations that are associated with synaptic and neuronal dysfunction in AD.
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DOI：
10.1523/jneurosci.0203-11.2011
发表时间：
2011-05-04
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Li S;Jin M;Koeglsperger T;Shepardson NE;Shankar GM;Selkoe DJ
通讯作者：
Selkoe DJ
影响因子：
2.5
作者：
Ranciat-McComb, NS;Bland, KS;Michaelis, ML
通讯作者：
Michaelis, ML
影响因子：
7.7
作者：
Pooler, Amy M.;Phillips, Emma C.;Lau, Dawn H. W.;Noble, Wendy;Hanger, Diane P.
通讯作者：
Hanger, Diane P.
星形胶质细胞是Aβ诱导的神经毒性和TAU磷酸化的重要介体。
影响因子：
9
作者：
通讯作者：
--
DOI：
10.1523/jneurosci.4119-08.2008
发表时间：
2008-11-19
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
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
通讯作者：
Nixon RA