Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid β-peptide-induced neuronal apoptosis -: Synergistic involvement of calpain and caspase-3
Microtubule-associated protein MAP1A, MAP1B, and MAP2 proteolysis during soluble amyloid β-peptide-induced neuronal apoptosis -: Synergistic involvement of calpain and caspase-3
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DOI：
10.1074/jbc.m507378200
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发表时间：
2006-01-06
影响因子：
4.8
通讯作者：
Pillot, T
中科院分区：
文献类型：
--
作者：
Fifre, A;Sponne, I;Pillot, T
越来越多的证据支持这一观点，即可溶性寡聚形式的淀粉样β-肽（Aβ）可能是阿尔茨海默病早期神经元损伤和死亡的直接效应物。然而，与可溶性Aβ诱导的神经元凋亡相关的分子机制仍有待阐明。我们最近证明了微管网络早期活性氧依赖性扰动的参与（Sponne, I.、Fifre, A.、Drouet, B.、Klein, C.、Koziel, V.、Pincon-Raymond, M.、Olivier, J.-L.、Chambaz, J. 和 Pillot, T. (2003) J. Biol. Chem. 278， 3437-3445）。由于微管相关蛋白 (MAP) 负责微管网络的聚合、稳定和动态，因此我们研究了 MAP 是否可能代表细胞内靶标，从而使我们能够解释可溶性 Aβ 介导的神经元凋亡中涉及的微管扰动。这里提供的数据表明，可溶性 A beta 寡聚物诱导 MAP1A、MAP1B 和 MAP2 的时间依赖性降解，涉及 Ca2+ 稳态的扰动以及随后的钙蛋白酶激活，其本身足以诱导亚型 MAP2a、MAP2b 和 MAP2c 的蛋白水解。相反，MAP1A 和 MAP1B 顺序蛋白水解是由 Aβ 介导的 caspase-3 和钙蛋白酶激活引起的。抗氧化剂对 MAP1A、MAP1B 和 MAP2 蛋白水解的预防凸显了可溶性 Aβ 诱导的微管网络扰动中早期活性氧的产生。这些数据清楚地证明了细胞骨架扰动对可溶性 Aβ 介导的细胞死亡的影响，并支持微管稳定剂作为有效阿尔茨海默病药物的概念。
A growing body of evidence supports the notion that soluble oligomeric forms of the amyloid beta-peptide (A beta) may be the proximate effectors of neuronal injuries and death in the early stages of Alzheimer disease. However, the molecular mechanisms associated with neuronal apoptosis induced by soluble A beta remain to be elucidated. We recently demonstrated the involvement of an early reactive oxygen species-dependent perturbation of the microtubule network (Sponne, I., Fifre, A., Drouet, B., Klein, C., Koziel, V., Pincon-Raymond, M., Olivier, J.-L., Chambaz, J., and Pillot, T. ( 2003) J. Biol. Chem. 278, 3437-3445). Because microtubule-associated proteins (MAPs) are responsible for the polymerization, stabilization, and dynamics of the microtubule network, we investigated whether MAPs might represent the intracellular targets that would enable us to explain the microtubule perturbation involved in soluble A beta-mediated neuronal apoptosis. The data presented here show that soluble A beta oligomers induce a time-dependent degradation of MAP1A, MAP1B, and MAP2 involving a perturbation of Ca2+ homeostasis with subsequent calpain activation that, on its own, is sufficient to induce the proteolysis of isoforms MAP2a, MAP2b, and MAP2c. In contrast, MAP1A and MAP1B sequential proteolysis results from the A beta-mediated activation of caspase-3 and calpain. The prevention of MAP1A, MAP1B, and MAP2 proteolysis by antioxidants highlights the early reactive oxygen species generation in the perturbation of the microtubule network induced by soluble A beta. These data clearly demonstrate the impact of cytoskeletal perturbations on soluble A beta-mediated cell death and support the notion of microtubule-stabilizing agents as effective Alzheimer disease drugs.