Saito K, Elce J S, Hamos J E, Nixon R A
McLean Hospital, Belmont, MA 02178.
Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32. doi: 10.1073/pnas.90.7.2628.
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.
钙激活中性蛋白酶（CANPs 或钙蛋白酶）被认为是细胞内信号级联反应中的关键酶，也是钙诱导神经元变性的潜在介质。为了研究它们在阿尔茨海默病中的作用，我们在人类尸检大脑中鉴定出三种 μCANP（钙蛋白酶 I）同工型，分别对应一个 80 kDa 的前体和两种自溶激活的同工型（78 kDa 和 76 kDa）。作为阿尔茨海默病中 μCANP 体内活性变化的指标，通过免疫测定法测量了 22 例阿尔茨海默病患者和 18 例正常对照者选定脑区中 μCANP 的 76 kDa 激活同工型与其 80 kDa 前体的比例。阿尔茨海默病患者前额叶皮质中的这种 μCANP 激活率升高了 3 倍，但亨廷顿病患者中未升高。在阿尔茨海默病病理较轻且未导致明显神经元变性的脑区，激活率也显著升高，但程度较小。这些发现表明，μCANP 激活不仅仅是细胞变性的结果，可能与许多神经元在发生明显结构变化之前功能异常有关。CANPs 对细胞骨架和膜动力学的已知影响意味着，持续的 CANP 激活可能在导致最易受损神经元群体的突触丧失或细胞死亡之前，就促成神经原纤维病理改变和淀粉样前体蛋白异常加工。作为阿尔茨海默病潜在的治疗策略，对 CANP 系统进行药理学调节可能值得考虑。
