Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease
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DOI：
10.1172/jci34254
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发表时间：
2008-08-01
影响因子：
15.9
通讯作者：
Arancio, Ottavio
中科院分区：
文献类型：
--
作者：
Trinchese, Fabrizio;Fa, Mauro;Arancio, Ottavio
钙蛋白酶是一种钙依赖性酶，通过调节蛋白质水解活性来决定蛋白质的命运。calpain与记忆调节有关，是阿尔茨海默病（AD）发病的关键。当异常激活时，钙蛋白酶还可以启动神经元生存所必需的蛋白质降解。本研究表明，通过半胱氨酸蛋白酶抑制剂E64和高度特异性的钙蛋白酶抑制剂BDA-410抑制钙蛋白酶，可以恢复AD动物模型APP/PS1小鼠海马培养物和海马片中的正常突触功能。Calpain抑制还能改善APP/PS1小鼠的空间工作记忆和联想恐惧记忆。钙蛋白酶抑制剂的这些有益作用与恢复转录因子CREB的正常磷酸化水平和突触蛋白突触蛋白i的重新分配有关。因此，钙蛋白酶抑制剂可能有助于减轻AD患者的记忆丧失。
Calpains are calcium-dependent enzymes that determine the fate of proteins through regulated proteolytic activity. Calpains have been linked to the modulation of memory and are key to the pathogenesis of Alzheimer disease (AD). When abnormally activated, calpains can also initiate degradation of proteins essential for neuronal survival. Here we show that calpain inhibition through E64, a cysteine protease inhibitor, and the highly specific calpain inhibitor BDA-410 restored normal synaptic function both in hippocampal cultures and in hippocampal slices from the APP/PS1 mouse, an animal model of AD. Calpain inhibition also improved spatial-working memory and associative fear memory in APP/PS1 mice. These beneficial effects of the calpain inhibitors were associated with restoration of normal phosphorylation levels of the transcription factor CREB and involved redistribution of the synaptic protein synapsin I. Thus, calpain inhibition may prove useful in the alleviation of memory loss in AD.