Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease
Correlation between caspase activation and neurofibrillary tangle formation in Alzheimer's disease
复制标题
DOI：
10.1016/s0002-9440(10)63957-0
复制
发表时间：
2001-01-01
影响因子：
6
通讯作者：
Cribbs, DH
中科院分区：
文献类型：
--
作者：
Rohn, TT;Head, E;Cribbs, DH
尽管有证据表明神经原纤维缠结(NFTs)和神经元Tell丢失是阿尔茨海默病(AD)的显著特征，但两者之间的关系尚不清楚。在本研究中，我们使用caspase裂解定点抗体来研究AD中细胞凋亡机制的激活与NFT形成之间的关系。该抗体识别caspase-3消化后的Fodrin裂解产物，但不识别全长Fodrin。ITT体外分析这种半胱氨酸天冬氨酸氨基转移酶裂解产物(CCP)抗体表明，它是一种检测培养神经元中的凋亡而不是坏死途径的特异性探针。为了确定半胱氨酸天冬氨酸氨基转移酶是否在体内裂解纤维蛋白，对对照组和阿尔茨海默病患者的组织切片进行纤维蛋白(CCP)免疫组织化学染色。尽管在对照组中没有观察到染色，但在所有AD患者的海马区都观察到了神经元的标记，随着疾病的进展，神经元的标记增加。为了确定caspase激活和NFT形成之间的可能关系，进行了fodrin CCP和PHF-1的双标记实验。定量分析显示，随着NFT形成程度的增加，Fodrin CCP免疫标记显著增加(r=0.84)。综上所述，这些结果为AD脑内神经元凋亡机制的激活提供了证据，并提示NFT的形成与AD细胞凋亡通路的激活之间存在关联。
Although evidence suggests that neurofibrillary tangles (NFTs) and neuronal tell loss are prominent features of Alzheimer's disease (AD), the relationship between the two remains unknown. In the present study, the relationship between the activation of apoptotic mechanisms and NFT formation in AD was investigated using a caspase-cleavage site-directed antibody to fodrin, an abundant neuronal cytoskeleton protein. This antibody recognized cleavage products of fodrin after digestion by caspase-3, but did not recognize full-length fodrin. Itt vitro analysis of this fodrin caspase-cleavage product (CCP) antibody demonstrates that it is a specific probe for the detection of apoptotic but not necrotic pathways in cultured neurons. To determine whether caspases cleave fodrin in vivo, tissue sections from controls and AD were immunostained for fodrin (CCPs). Although no staining was observed in control cases, labeling of neurons was observed in the hippocampus of all AD cases, which increased as a function of disease progression. To determine a possible relationship between caspase activation and NFT formation, double-labeling experiments with fodrin CCP and PHF-1 were performed. Co-localization of these markers was observed in many neurons, and quantitative analysis showed that as the extent of NFT formation increased, there was a significant corresponding increase in fodrin CCP immunolabeling (r = 0.84). Taken together, these results provide evidence for the activation of apoptotic mechanisms in neurons in the AD brain and suggest that there is an association between NFT formation and the activation of apoptotic pathways in AD.