Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice
Increased vulnerability of hippocampal neurons to excitotoxic necrosis in presenilin-1 mutant knock-in mice
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DOI：
10.1038/4789
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发表时间：
1999-01-01
期刊：
影响因子：
82.9
通讯作者：
Mattson, MP
中科院分区：
文献类型：
--
作者：
Guo, Q;Fu, WM;Mattson, MP
兴奋性毒性是一种神经元损伤形式，谷氨酸受体的过度激活导致细胞钙超载(1，2)，已被认为与阿尔茨海默病(3，4)(AD)的发病机制有关，尽管缺乏直接证据。14号染色体上早老素-1(PS1)基因的突变与许多早发性遗传性AD有因果关系。5、6)。我们产生了PS1突变小鼠(PS1M146VKI)，它们在正常生理水平上表达PS1 M146V靶基因。虽然PS1M146VKI小鼠没有明显的突变表型，但它们对癫痫诱导的突触变性和海马神经元坏死性死亡高度敏感。培养的PS1M146VKI小鼠海马神经元对谷氨酸诱导的死亡的易感性增加，这与钙稳态被扰乱、氧化应激增加和线粒体功能障碍有关。抑制钙内流或钙释放的药物和抗氧化剂保护神经元免受PS1突变的兴奋毒性作用。这些发现建立了导致AD的遗传缺陷和兴奋性毒性神经元变性之间的直接联系，并为AD患者的治疗干预指明了新的途径。
Excitotoxicity, a form of neuronal injury in which excessive activation of glutamate receptors results in cellular calcium overload(1,2) has been implicated in the pathogenesis of Alzheimer disease(3,4) (AD), although direct evidence is lacking. Mutations in the presenilin-1 (PS1) gene on chromosome 14 are causally linked to many cases of early-onset inherited AD (refs. 5,6). We generated PS1 mutant mice (PS1M146VKI) that express the PS1 M146V targeted allele at normal physiological levels. Although PS1M146VKI mice have no overt mutant phenotype, they are hypersensitive to seizure-induced synaptic degeneration and necrotic neuronal death in the hippocampus. Cultured hippocampal neurons from PS1M146VKI mice have increased vulnerability to death induced by glutamate, which is correlated with perturbed calcium homeostasis, increased oxidative stress and mitochondrial dysfunction. Agents that suppress calcium influx or release and antioxidants protect neurons against the excitotoxic action of the PS1 mutation. These findings establish a direct link between a genetic defect that causes AD and excitotoxic neuronal degeneration, and indicate new avenues for therapeutic intervention in AD patients.