WIDESPREAD ACTIVATION OF CALCIUM-ACTIVATED NEUTRAL PROTEINASE (CALPAIN) IN THE BRAIN IN ALZHEIMER-DISEASE - A POTENTIAL MOLECULAR-BASIS FOR NEURONAL DEGENERATION
WIDESPREAD ACTIVATION OF CALCIUM-ACTIVATED NEUTRAL PROTEINASE (CALPAIN) IN THE BRAIN IN ALZHEIMER-DISEASE - A POTENTIAL MOLECULAR-BASIS FOR NEURONAL DEGENERATION
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DOI：
10.1073/pnas.90.7.2628
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发表时间：
1993-04-01
影响因子：
11.1
通讯作者：
NIXON, RA
中科院分区：
文献类型：
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作者：
SAITO, KI;ELCE, JS;NIXON, RA
钙激活中性蛋白酶（CANP或calpains）被认为是细胞内信号级联的关键酶和钙诱导的神经元变性的潜在介质。为了研究他们参与阿尔茨海默病，我们确定了三种异构体muCANP（钙蛋白酶I）在人类死后的大脑对应于一个80 kDa的前体和两个自溶激活的异构体（78和76 kDa）。作为阿尔茨海默病中muCANP体内活性变化的指标，通过免疫测定法在来自22名阿尔茨海默病患者和18名正常对照的选定脑区域中测量muCANP的76-kDa活化同种型与其80-kDa前体的比率。这种muCANP激活率在阿尔茨海默病患者的前额皮质中升高3倍，但在亨廷顿病患者中没有。激活率也显著升高，但在阿尔茨海默病病理学较轻且未导致明显神经元变性的脑区域中程度较低。这些发现表明，muCANP激活不仅是细胞变性的结果，而且可能与许多神经元在总体结构变化发生之前的功能障碍有关。CANP对细胞骨架和膜动力学的已知影响意味着持续的CANP激活可能在导致最脆弱的神经元群体中的突触丧失或细胞死亡之前促成神经病理学和异常淀粉样前体蛋白加工。CANP系统的药理学调节可能值得考虑作为阿尔茨海默病的潜在治疗策略。
Calcium-activated neutral proteinases (CANPs or calpains) are believed to be key enzymes in intracellular signaling cascades and potential mediators of calcium-induced neuronal degeneration. To investigate their involvement in Alzheimer disease, we identified three isoforms of muCANP (calpain I) in human postmortem brain corresponding to an 80-kDa precursor and two autolytically activated isoforms (78 and 76 kDa). As an index of changes in the in vivo activity of muCANP in Alzheimer disease, the ratio of the 76-kDa activated isoform of muCANP to its 80-kDa precursor was measured by immunoassay in selected brain regions from 22 individuals with Alzheimer disease and 18 normal controls. This muCANP activation ratio was elevated 3-fold in the prefrontal cortex from patients with Alzheimer disease but not from patients with Huntington disease. The activation ratio was also significantly elevated, but to a lesser degree, in brain regions where Alzheimer pathology is milder and has not led to overt neuronal degeneration. These findings indicate that muCANP activation is not simply a consequence of cellular degeneration but may be associated with dysfunction in many neurons before gross structural changes occur. The known influences of CANPs on cytoskeleton and membrane dynamics imply that persistent CANP activation may contribute to neurofibrillary pathology and abnormal amyloid precursor protein processing prior to causing synapse loss or cell death in the most vulnerable neuronal populations. Pharmacological modulation of the CANP system may merit consideration as a potential therapeutic strategy in Alzheimer disease.