Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration
Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration
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DOI：
10.1016/s0896-6273(04)00182-5
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发表时间：
2004-04-08
期刊：
影响因子：
16.2
通讯作者：
Shen, J
中科院分区：
文献类型：
--
作者：
Saura, CA;Choi, SY;Shen, J
早老素突变是家族性阿尔茨海默病的主要原因，但早老素突变导致记忆丧失和神经退行性变的致病机制仍不清楚。在这里，我们证明了条件性双基因敲除小鼠出生后前脑既缺乏早老素表现出海马记忆和突触可塑性的损害。这些缺陷与NMDA受体介导的反应和NMDA受体和alphaCaMKII的突触水平的特异性降低相关。此外，早老素的缺失导致CBP和CREB/CBP靶基因（如c-fos和BDNF）的表达减少。随着年龄的增长，突变小鼠的大脑皮层发生显著的神经退行性变，记忆和突触功能的损害恶化。神经变性伴随着Cdk 5激活剂p25和过度磷酸化tau水平的增加。这些结果定义了早老素在突触可塑性、学习和记忆以及成年大脑皮层神经元存活中的重要作用和分子靶点。
Mutations in presenilins are the major cause of familial Alzheimer's disease, but the pathogenic mechanism by which presenilin mutations cause memory loss and neurodegeneration remains unclear. Here we demonstrate that conditional double knockout mice lacking both presenilins in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic plasticity. These deficits are associated with specific reductions in NMDA receptor-mediated responses and synaptic levels of NMDA receptors and alphaCaMKII. Furthermore, loss of presenilins causes reduced expression of CBP and CREB/CBP target genes, such as c-fos and BDNF. With increasing age, mutant mice develop striking neurodegeneration of the cerebral cortex and worsening impairments of memory and synaptic function. Neurodegeneration is accompanied by increased levels of the Cdk5 activator p25 and hyperphosphorylated tau. These results define essential roles and molecular targets of presenilins in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex.