Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites.
Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites.
复制标题
DOI：
--
复制
发表时间：
1998
期刊：
影响因子：
2.9
通讯作者：
M. Mattson;J. Partin;J. Begley
中科院分区：
文献类型：
--
作者：
M. Mattson;J. Partin;J. Begley
大脑皮层和海马中的突触丢失是阿尔茨海默病（AD）的显著特征，其与认知损害相关。树突的突触后区域由于谷氨酸受体的局部激活而受到特别高水平的钙内流和氧化应激，因此可能是AD中神经退行性过程起始的位点。数据表明，AD中的神经元可能通过称为细胞凋亡的过程死亡，该过程涉及一系列定型的生化变化，最终导致核碎裂，并且淀粉样β肽（Abeta）可能在这种细胞凋亡中发挥作用。我们现在报告，Abeta诱导皮质突触体和培养的海马神经元树突中的突触相关的生化变化。突触体暴露于Abeta导致膜磷脂不对称性丧失、半胱天冬酶激活和线粒体膜去极化。暴露于Abeta的突触体的胞质提取物诱导分离的核中的染色质凝聚和碎裂，表明能够诱导核凋亡的信号可以在突触中局部产生。培养的海马神经元暴露于Abeta导致半胱天冬酶激活和树突和细胞体中的线粒体膜去极化。一种半胱天冬酶抑制剂阻止了A β诱导的突触体线粒体膜去极化，以及培养的海马神经元线粒体膜去极化和核凋亡。总的来说，这些数据表明，凋亡的生化级联反应可以激活突触和树突的Abeta，并表明，这种“突触凋亡”可能有助于突触功能障碍和退化的AD。
Synapse loss in cerebral cortex and hippocampus is a prominent feature of Alzheimer's disease (AD) that is correlated with cognitive impairment. Postsynaptic regions of dendrites are subjected to particularly high levels of calcium influx and oxidative stress as a result of local activation of glutamate receptors, and are therefore likely to be sites at which neurodegenerative processes are initiated in AD. Data suggest that neurons may die in AD by a process called apoptosis which involves a stereotyped series of biochemical changes that culminate in nuclear fragmentation, and that amyloid beta-peptide (Abeta) may play a role in such apoptosis. We now report that Abeta induces apoptosis-related biochemical changes in cortical synaptosomes, and in dendrites of cultured hippocampal neurons. Exposure of synaptosomes to Abeta resulted in loss of membrane phospholipid asymmetry, caspase activation, and mitochondrial membrane depolarization. Cytosolic extracts from synaptosomes exposed to Abeta induced chromatin condensation and fragmentation in isolated nuclei indicating that signals capable of inducing nuclear apoptosis can be generated locally in synapses. Exposure of cultured hippocampal neurons to Abeta resulted in caspase activation and mitochondrial membrane depolarization in dendrites and cell bodies. A caspase inhibitor prevented Abeta-induced mitochondrial membrane depolarization in synaptosomes, and mitochondrial membrane depolarization and nuclear apoptosis in cultured hippocampal neurons. Collectively, the data demonstrate that apoptotic biochemical cascades can be activated in synapses and dendrites by Abeta, and suggest that such 'synaptic apoptosis' may contribute to synaptic dysfunction and degeneration in AD.