アルツハイマー病アミロイド・ベーター蛋白の毒性発現の抑制機構(メタロチオネイン及びその類似蛋白とアルミニウムの影響)

老年斑是阿尔茨海默病(AD)的主要病理标志。它们含有β-淀粉样蛋白(βA)，来源于淀粉样前体蛋白(APP)。βA被认为与该病的发病机制有关，但其神经毒性机制尚不清楚。积累的铝和凝血酶被认为是βA在神经元中的一种中毒原因。最近，一种与βA结合并介导AD神经毒性的细胞内蛋白-ERAB(内质网相关结合蛋白)已被发现。寻找一种在神经细胞中诱导ERAB的方法。在第一个财政年度(1998年)，为了确定铝是否诱导ERAB mRNA，我们在含硫酸铝(500μM)的无血清RPMI1640培养液中培养神经母细胞瘤细胞(GOTO)12小时。经硫酸铝处理的细胞APP基因表达水平显著低于对照组。而硫酸铝对细胞ERAB基因表达水平无明显影响，表明铝不能诱导ERAB基因表达。在第二个财政年度(1999年)，为了确定凝血酶受体激活是否诱导ERAB基因的表达，我们在含有TRAP(凝血酶受体激活肽)(100μM)的无血清RPMI1640培养液中培养神经母细胞瘤细胞(GOTO)12h。经TRAP处理的细胞APP基因表达水平显著高于对照组。但TRAP对ERAB基因表达水平无明显影响，提示凝血酶受体激活并不诱导ERAB基因表达。综上所述，铝和凝血酶均不能诱导ERAB基因的表达，提示它们与AD的发病机制无关。

Senile plaques are a major pathological hallmark of Alzheimer's disease (AD). They contain β-amyloid protein (βA), derived from amyloid precursor protein (APP). βA is thought to contribute to the pathogenesis of the disease, but the mechanism of its neurotoxicity remains unknown. Accumulated aluminum and thrombin have been expected to predispose βA to a toxic cause in neurons. Recently, an intracellular protein that binds βA and mediates neurotoxicity in AD, ERAB (endoplasmic-reticulum-associated binding protein), has been identified. To find a method to induce ERAB in neuronal cells. In the first fiscal year (1998), to determine whether aluminum induces ERAB mRNA, we grew neuroblastoma cells (GOTO) in serum-free RPMI 1640 medium containing aluminum sulfate (500μM) for 12 hours. The cells exposed to aluminum sulfate showed significantly lower APP mRNA level than the control cells. However, the cells exposed to aluminum sulfate showed no significant change in ERAB mRNA level, indicating that aluminum does not induce ERAB mRNA. In the second fiscal year (1999), to determine whether thrombin receptor activation induces ERAB mRNA, we grew neuroblastoma cells (GOTO) in serum-free RPMI 1640 medium containing TRAP (thrombin receptor activating peptide) (100μM) for 12 hours. The cells exposed to TRAP showed significantly higher APP mRNA level than the control cells. However, the cells exposed to TRAP showed no significant change in ERAB mRNA level, indicating that thrombin receptor activation does not induce ERAB mRNA. In conclusion, neither aluminum nor thrombin induces ERAB mRNA, suggesting that they do not relate to the pathogenesis of AD via ERAB mRNA induction.