Department of Pharmacology, Tokyo Medical University, 6-1-1 Shinjuku, Tokyo 160-8402, Japan.
Biochem Biophys Res Commun. 2010 Mar 26;394(1):119-25. doi: 10.1016/j.bbrc.2010.02.127. Epub 2010 Feb 23.
Our earlier studies indicated that TGFbeta2-induced neuronal cell death by binding to the extracellular domain of amyloid beta precursor protein (APP) on the cell surface and by triggering an intracellular death signal pathway, mediated by a heterotrimeric G protein Go, Rac1/cdc42, ASK1, JNK, NADPH oxidase, and caspases in this order. Recently, transient axonal glycoprotein-1 (TAG-1), a glycophosphatidylinositol-linked protein, was identified as another natural ligand of APP. TAG-1 increases APP intracellular domain release and triggers FE65-dependent transcriptional activity in a gamma-secretase-dependent manner by binding to APP. In this study, we show that TAG-1 inhibits TGFbeta2-mediated neuronal cell death via APP by attenuating the binding of TGFbeta2 to APP in a gamma-secretase-independent manner. TAG-1 is expressed in murine hippocampal neurons at 8 weeks of age, but its expression is reduced at 8 and 20 months. These findings suggest that an age-related reduction of TAG-1 expression may predispose neurons to cell death, induced by the binding of TGFbeta2 to APP. This mechanism may contribute to the onset and the progression of Alzheimer's disease-relevant neuronal cell death.
我们之前的研究表明，TGFβ2 通过与细胞表面淀粉样前体蛋白（APP）的细胞外结构域结合，并通过引发由异三聚体 G 蛋白 Go、Rac1/cdc42、ASK1、JNK、NADPH 氧化酶和 caspase 依次介导的细胞内死亡信号通路，诱导神经元细胞死亡。最近，瞬时轴突糖蛋白-1（TAG-1），一种糖磷脂酰肌醇连接蛋白，被鉴定为 APP 的另一种天然配体。TAG-1 通过与 APP 结合，以 γ-分泌酶依赖性方式增加 APP 细胞内结构域的释放，并触发 FE65 依赖性转录活性。在这项研究中，我们表明，TAG-1 通过以 γ-分泌酶非依赖性方式减弱 TGFβ2 与 APP 的结合，抑制 TGFβ2 介导的神经元细胞死亡。TAG-1 在 8 周龄的小鼠海马神经元中表达，但在 8 个月和 20 个月时表达减少。这些发现表明，TAG-1 表达的年龄相关性降低可能使神经元易受 TGFβ2 与 APP 结合诱导的细胞死亡的影响。这种机制可能有助于阿尔茨海默病相关神经元细胞死亡的发生和进展。
