Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease
Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease
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DOI：
10.1038/nn.2709
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发表时间：
2011-01-01
影响因子：
25
通讯作者：
Cecconi, Francesco
中科院分区：
文献类型：
--
作者：
D'Amelio, Marcello;Cavallucci, Virve;Cecconi, Francesco
突触丧失是阿尔茨海默病认知功能下降的最佳病理相关性;然而，突触失效的分子机制尚不清楚。我们发现海马树突棘中的非凋亡基线半胱天冬酶-3活性和在阿尔茨海默病的Tg 2576-APPswe小鼠模型中记忆下降开始时这种活性的增强。在脊髓中，caspase-3激活钙调神经磷酸酶，这反过来又触发了去磷酸化和AMPA型受体的GluR 1亚基从突触后位点的去除。这些分子修饰导致谷氨酸能突触传递和可塑性的改变，并与脊柱变性和海马依赖性记忆缺陷相关。值得注意的是，药理学抑制胱天蛋白酶-3活性在Tg 2576小鼠中拯救了观察到的阿尔茨海默病样表型。我们的研究结果确定了一个以前未知的caspase-3依赖性机制，驱动突触失败，并有助于阿尔茨海默病的认知功能障碍。这些发现表明，caspase-3是一个潜在的目标，在疾病的早期阶段的药物治疗。
Synaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's disease; however, the molecular mechanisms underlying synaptic failure are unknown. We found a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's disease. In spines, caspase-3 activated calcineurin, which in turn triggered dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from postsynaptic sites. These molecular modifications led to alterations of glutamatergic synaptic transmission and plasticity and correlated with spine degeneration and a deficit in hippocampal-dependent memory. Notably, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescued the observed Alzheimer-like phenotypes. Our results identify a previously unknown caspase-3-dependent mechanism that drives synaptic failure and contributes to cognitive dysfunction in Alzheimer's disease. These findings indicate that caspase-3 is a potential target for pharmacological therapy during early disease stages.