Saura Carlos A, Choi Se-Young, Beglopoulos Vassilios, Malkani Seema, Zhang Dawei, Shankaranarayana Rao B S, Chattarji Sumantra, Kelleher Raymond J, Kandel Eric R, Duff Karen, Kirkwood Alfredo, Shen Jie
Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Neuron. 2004 Apr 8;42(1):23-36. doi: 10.1016/s0896-6273(04)00182-5.
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.
早老素突变是家族性阿尔茨海默病的主要病因，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。在此，我们证明，出生后前脑同时缺乏两种早老素的条件性双敲除小鼠表现出海马记忆和突触可塑性受损。这些缺陷与NMDA受体介导的反应以及NMDA受体和αCaMKII的突触水平的特异性降低有关。此外，早老素的缺失导致CBP以及CREB/CBP靶基因（如c-fos和BDNF）的表达减少。随着年龄的增长，突变小鼠出现明显的大脑皮质神经退行性变，记忆和突触功能障碍也日益加重。神经退行性变伴随着Cdk5激活剂p25水平的升高和tau蛋白的过度磷酸化。这些结果确定了早老素在成年大脑皮质的突触可塑性、学习和记忆以及神经元存活中的重要作用和分子靶点。
