Rees T, Hammond P I, Soreq H, Younkin S, Brimijoin S
Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Mayo Medical School, Rochester, MN 55905, USA.
Neurobiol Aging. 2003 Oct;24(6):777-87. doi: 10.1016/s0197-4580(02)00230-0.
Studies in vitro have suggested that acetylcholinesterase (AChE) may interact with beta-amyloid to promote deposition of amyloid plaques in the brain of patients with Alzheimer's disease. To test that hypothesis in vivo, we crossed Tg2576 mice, which express human amyloid precursor protein and develop plaques at 9 months, with transgenic mice expressing human AChE. The resulting F1 hybrids (FVB/N x [C57B6 x SJL/J]) expressed both transgenes in brain. By 6 months of age, their cerebral cortex showed authentic plaques that stained both by thioflavin S and by beta-amyloid 1-40 and 1-42 immunohistochemistry. The plaques also stained positively for other components including Cd11b, GFAP, and AChE. Plaque onset in the hybrids occurred 30-50% sooner than in the parental lines. Plaque numbers increased with age and plaques remained more numerous in the doubly transgenic animals at 9 and 12 months. Quantitative immunoassay via ELISA also showed an increase of total amyloid content in brain at 9-12 months. These histological and biochemical results support the conclusion that AChE may play a role in pathogenesis of Alzheimer's disease
体外研究表明，乙酰胆碱酯酶（AChE）可能与β-淀粉样蛋白相互作用，促进阿尔茨海默病患者大脑中淀粉样斑块的沉积。为了在体内验证这一假设，我们将表达人淀粉样前体蛋白并在9个月时出现斑块的Tg2576小鼠与表达人AChE的转基因小鼠进行杂交。所得的F1代杂种（FVB/N×[C57B6×SJL/J]）在大脑中同时表达这两种转基因。到6个月大时，它们的大脑皮层出现了经硫黄素S以及β-淀粉样蛋白1-40和1-42免疫组织化学染色的典型斑块。这些斑块对包括Cd11b、GFAP和AChE在内的其他成分也呈阳性染色。杂种小鼠中斑块的出现比亲本品系早30%-50%。斑块数量随年龄增加，在9个月和12个月时，双转基因动物中的斑块数量仍然更多。通过酶联免疫吸附测定（ELISA）进行定量免疫分析也显示，9至12个月时大脑中总淀粉样蛋白含量增加。这些组织学和生化结果支持以下结论：AChE可能在阿尔茨海默病的发病机制中起作用。
