Toxicology Laboratory, Shenzhen Centre for Disease Control and Prevention, 8 Longyuan Road, Nanshan District, 518055 Shenzhen, China.
Neurochem Res. 2012 Jan;37(1):15-22. doi: 10.1007/s11064-011-0575-2. Epub 2011 Aug 13.
Mutations in presenilin 1 (PS-1) are associated with most early-onset familiar Alzheimer's disease (AD). Previous studies have demonstrated that PS-1 mutations enhance the production of beta-amyloid (Aβ). In this study, we further examined the in vivo effects of PS-1 mutation on tau and synapse protein markers. The data showed that the phosphorylation of tau at Ser396, Ser404, Thr231 and Tau-1 (Ser198/199/202) epitopes was significantly increased in hippocampus of the aged (twenty-one and a half-month-old) transgenic mice expressing PS-1 (L235P) compared to that of the age-matched wild-type littermates (WTs). Concurrently, a significant decrease in the phosphorylation of glycogen synthase kinase (GSK)-3β at Ser9 was observed. The above changes were not observed in the young transgenic mice (6-8 months old). No significant changes in the levels of cyclin-dependent kinase (CDK)-5, its co-activator p35, and phosphorylation of protein phosphatase (PP)-2A catalytic subunit at Tyrosine 307 (Y307), a crucial site regulating the activity of PP-2A, were observed both in the young and aged transgenic mice compared to that of WTs. Furthermore, we also observed that the levels of presynaptic synaptophysin were significantly decreased but postsynaptic density protein (PSD)-95 were not significantly altered in hippocampus of the aged transgenic mice. No significant changes of synaptophysin or PSD-95 were observed in the brains of the young transgenic mice. Our data indicate that the L235P PS-1 mutation can induce Alzheimer-like tau hyperphosphorylation and synaptic protein loss, as well as increased production of Aβ.
早发型家族性阿尔茨海默病（AD）的发生与早老素 1（PS-1）基因突变密切相关。既往研究表明 PS-1 基因突变可增强β-淀粉样蛋白（Aβ）的产生。本研究进一步观察了 PS-1 突变对 tau 和突触蛋白标志物的体内影响。结果显示，与年龄匹配的野生型同窝仔鼠（WTs）相比，在表达 PS-1（L235P）的老年（21.5 月龄）转基因鼠海马中 tau 的 Ser396、Ser404、Thr231 和 Tau-1（Ser198/199/202）表位磷酸化显著增加。同时，观察到糖原合酶激酶（GSK）-3β在 Ser9 的磷酸化显著减少。上述变化在年轻的转基因鼠（6-8 月龄）中未观察到。与 WTs 相比，年轻和老年转基因鼠中 cyclin-dependent kinase（CDK）-5 及其共激活子 p35、调节蛋白磷酸酶（PP）-2A 活性的关键位点 Tyr307 磷酸化的 PP-2A 催化亚单位的水平均无显著变化。此外，我们还观察到在老年转基因鼠海马中，突触小体相关蛋白 synaptophysin 的水平显著降低，但突触后密度蛋白（PSD）-95 无明显改变。年轻的转基因鼠脑内 synaptophysin 或 PSD-95 无明显变化。我们的数据表明，L235P PS-1 突变可诱导类似阿尔茨海默病的 tau 过度磷酸化和突触蛋白丢失，以及 Aβ的产生增加。
