期刊
JOURNAL OF NEUROCHEMISTRY
卷 121, 期 1, 页码 135-145出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2011.07489.x
关键词
glycogen synthase kinase-3; presenilin-1; spatial memory; tau hyperphosphorylation; Val97Leu mutation
资金
- National Key Technology RD Program [2006BAI02B01]
- National Natural Science Foundation of China [30830045, 81000472]
- National Basic Research 973 Program [2006CB500700]
- National High Technology Research and Development Program 863 [2006AA02A408]
- Beijing Natural Science Foundation [7102071]
- Beijing Municipal Education Commission [KZ200910025005]
Although the pathological role of presenilin-1 mutation in early onset familial Alzheimers disease has been widely studied, few focused on how the presenilin-1 mutations result in memory impairment and tau hyperphosphorylation. In the present study, we expressed human Val97Leu mutant presenilin-1, which is reported in Chinese pedigrees by our group, in transgenic mice and found that the mutant presenilin-1 induced spatial memory deficit and tau hyperphosphorylation at PHF-1, pS199/202, pT231 and pS396 epitopes, but not at pS214 and pS422 epitopes. Pearson analysis showed that the memory deficit was only significantly correlated with tau phosphorylation level at PHF-1, pS199/202, pT231 and pS396 epitopes. Additionally, the hyperphosphorylated tau and tangle-like argentophilic structures were detected at CA3 and CA4, but not CA1, region of hippocampus, and we also found tangle-like structure and wizened degenerative neurons in frontal cortex. We demonstrated the tau hyperphosphorylation at the same epitopes in N2a cells expressing the mutant presenilin-1, which is caused by inhibition of phosphoinositol-3 kinase/Akt and activation of glycogen synthase kinase-3 specifically. Our data demonstrated that human Val97Leu mutant presenilin-1 causes spatial memory deficit in mice and increases tau phosphorylation level in glycogen synthase kinase-3-dependent manner.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据