Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology
Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology
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DOI：
10.1096/fj.11-187740
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发表时间：
2012-03-01
期刊：
影响因子：
4.8
通讯作者：
Saido, Takaomi C.
中科院分区：
文献类型：
--
作者：
Higuchi, Makoto;Iwata, Nobuhisa;Saido, Takaomi C.
淀粉样β肽（A β）积累导致阿尔茨海默病（AD）神经退行性变的机制尚未解决。鉴于A β扰乱神经元中的钙稳态，我们研究了钙蛋白酶（一种钙激活的中性蛋白酶）的可能参与。我们首先证明了AD患者和过表达淀粉样前体蛋白（APP）的转基因（Tg）小鼠大脑中钙蛋白酶激活与A β斑块形成的密切突触后联系。使用病毒载体为基础的示踪剂，我们然后表明，轴突末端动态误导钙蛋白酶激活阳性A β斑块。一致的是，AD患者的脑脊液中钙蛋白酶裂解血影蛋白的水平高于对照组。钙蛋白酶抑制蛋白（CS）（一种钙蛋白酶特异性抑制剂蛋白）的遗传缺陷可增强A β淀粉样变性、tau蛋白磷酸化、小胶质细胞增生和体细胞树突状营养不良，并增加APP-Tg小鼠的死亡率。相反，脑特异性CS过表达具有相反的效果。这些发现表明钙蛋白酶激活在A β触发的病理级联反应中起着关键作用，突出了AD治疗中药理学干预的目标。Higuchi，M.，美国，岩田，N.，Matsuba，Y.，Takano，J.，末本，T.，Maeda，J.，Ji，B.，Ono，M.，Staufenbiel，M.，Suhara，T.，Saido，T. C.钙蛋白酶-钙蛋白酶抑制蛋白系统参与阿尔茨海默病神经病理学的机制FASEB J.26，1204-1217（2012）。www.fasebj.org
The mechanism by which amyloid-beta peptide (A beta) accumulation causes neurodegeneration in Alzheimer's disease (AD) remains unresolved. Given that A beta perturbs calcium homeostasis in neurons, we investigated the possible involvement of calpain, a calcium-activated neutral protease. We first demonstrated close postsynaptic association of calpain activation with A beta plaque formation in brains from both patients with AD and transgenic (Tg) mice overexpressing amyloid precursor protein (APP). Using a viral vector-based tracer, we then showed that axonal termini were dynamically misdirected to calpain activation-positive A beta plaques. Consistently, cerebrospinal fluid from patients with AD contained a higher level of calpain-cleaved spectrin than that of controls. Genetic deficiency of calpastatin (CS), a calpain-specific inhibitor protein, augmented A beta amyloidosis, tau phosphorylation, microgliosis, and somatodendritic dystrophy, and increased mortality in APP-Tg mice. In contrast, brain-specific CS overexpression had the opposite effect. These findings implicate that calpain activation plays a pivotal role in the A beta-triggered pathological cascade, highlighting a target for pharmacological intervention in the treatment of AD.-Higuchi, M., Iwata, N., Matsuba, Y., Takano, J., Suemoto, T., Maeda, J., Ji, B., Ono, M., Staufenbiel, M., Suhara, T., Saido, T. C. Mechanistic involvement of the calpain-calpastatin system in Alzheimer neuropathology. FASEB J. 26, 1204-1217 (2012). www.fasebj.org