Reduced β-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice
Reduced β-amyloid production and increased inflammatory responses in presenilin conditional knock-out mice
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DOI：
10.1074/jbc.m409544200
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发表时间：
2004-11-05
影响因子：
4.8
通讯作者：
Shen, J
中科院分区：
文献类型：
--
作者：
Beglopoulos, V;Sun, XY;Shen, J
早老素(PS)1和2的突变是家族性阿尔茨海默病的主要原因。在出生后前脑中缺乏两种早老素的条件性双基因敲除小鼠(PS cDKO小鼠)表现出记忆和突触可塑性障碍，随后大脑皮层出现进行性神经变性。在这里，我们进一步研究可能是观察到的表型背后的分子事件，并在PS cDKO脑中识别其他神经病理标记物。酶联免疫吸附分析显示，PS cDKO小鼠大脑皮层中有毒的β-淀粉样多肽(Abeta)水平降低。有趣的是，在PS1条件性基因敲除和PS cDKO小鼠中，Abeta40和Abeta42肽的减少是相似的。我们进一步用寡核苷酸芯片检测了PS cDKO大脑皮层的基因表达谱，发现有大量的基因有差异表达，最显著的是一组上调的炎症基因。实时定量逆转录聚合酶链式反应和Western分析证实，胶质纤维酸性蛋白、补体成分C1q和组织蛋白酶S水平升高，它们的上调与各种神经退行性变过程中的炎症反应有关。免疫组织化学分析表明，补体成分C1q的增加仅限于海马区，而胶质纤维酸性蛋白和组织蛋白酶S在整个新皮质和海马区表达上调。此外，PS cDKO小鼠的海马区和更深层的皮质层也有很强的小胶质细胞激活。这些结果表明，PS cDKO小鼠的记忆障碍和神经变性不是由Abeta蓄积引起的，PS功能的丧失导致大脑皮层炎症标志物的差异上调。
Mutations in presenilins ( PS) 1 and 2 are the major cause of familial Alzheimer's disease. Conditional double knock-out mice lacking both presenilins in the postnatal forebrain (PS cDKO mice) exhibit memory and synaptic plasticity impairments followed by progressive neurodegeneration in the cerebral cortex. Here we further investigate the molecular events that may underlie the observed phenotypes and identify additional neuropathological markers in the PS cDKO brain. Enzyme-linked immunosorbent assay analysis showed reduced levels of the toxic beta-amyloid (Abeta) peptides in the cerebral cortex of PS cDKO mice. Interestingly, the reduction in Abeta40 and Abeta42 peptides is similar in PS1 conditional knock-out and PS cDKO mice. We further examined the gene expression profile by oligonucleotide microarrays in the PS cDKO cerebral cortex and found that a high number of genes are differentially expressed, most notably a group of upregulated inflammatory genes. Quantitative real-time reverse transcription PCR and Western analyses confirmed the elevated levels of glial fibrillary acidic protein, complement component C1q, and cathepsin S, up-regulation of which has been associated with inflammatory responses in various neurodegenerative processes. Immunohistochemical analysis revealed that the increase in complement component C1q is confined to the hippocampal formation, whereas glial fibrillary acidic protein and cathepsin S are up-regulated throughout the entire neocortex and hippocampus. In addition, strong microglial activation occurs in the hippocampus and the deeper cortical layers of PS cDKO mice. These results indicate that the memory impairment and neurodegeneration in PS cDKO mice are not caused by Abeta accumulation and that loss of PS function leads to differential up-regulation of inflammatory markers in the cerebral cortex.