Development of treatment for Alzheimer's disease using transgenic animal models.

1)Tg2576的记忆障碍在淀粉样斑块出现之前就已开始，并与脑组织中乙酰胆碱的选择性降低有关。由于Tg2576几乎复制了阿尔茨海默病脑内除神经原纤维缠结外的所有病理改变，因此Tg2576是评价乙酰胆碱酯酶抑制剂作用的良好动物模型。2)双转基因小鼠(Tg2576xPS-1L286V)表现出广泛的Aβ淀粉样蛋白沉积加速，并导致继发性转位性病变。在年长的双转基因小鼠中，观察到直小管。3)A-β-40和A-β-42抗体注射后，A-β浓度分别提高了~5倍，提示这些特异性抗体的被动免疫可以减轻脑内A-β负担。这些抗体可以减少Aβ原纤维和Aβ寡聚体，并改善组织学淀粉样斑块出现之前的记忆障碍。4)我们发现Aβ二聚体作为淀粉样蛋白的启动因子在TG和AD脑中的脂筏中开始积聚，这些发现表明Aβ在脂筏中的积聚是治疗的一个重要靶点。在脂筏中，AopE和磷酸化tau在TG和AD脑中有次级积聚。5)褪黑素可降低TG脑内Aβ负荷，改善TG的记忆障碍。还观察到提高存活率和氧化能力。目前正在计划临床应用。6)辛伐他汀不能改善TG脑内Aβ负荷。然而，在脂筏水平上，胆固醇依赖的β分泌酶对Aγ生成的调节是可能的。在AopE调整后的1800例尸检队列中，成年早期高胆固醇血症是AD的危险因素。这些发现表明，高舞蹈性固醇血症的治疗对AD的发病具有保护作用。前瞻性多中心研究，阐明斑点对AD的影响应在细胞和动物模型水平进行研究。

1) Memory disturbance of Tg2576 initiated before amyloid plaque appearance and correlated with selective decrease of acetylcholine in the brain. Since Tg2576 reproduced almost all pathological alterations of Alzheimer's brains except neurofibrillary tangles, Tg2576 is an excellent animal model for evaluation of the effects of acetylcholine esterase inhibitors. 2) Double transgenic mouse (Tg2576xPS-1 L286V) showed extensive acceleration of Aβ amyloid deposits and induced secondary tauopathy. In elder double transgenic mice, straight tubules were observed. 3) Injections of antibodies to Aβ40 and Aβ42 increased 〜5 times of plasma Aβ concentrations respectively, suggesting that passive immunization using these specific antibodies can clear brain Aβ burden. These antibodies may decrease Aβ protofibril and Aβ oligomers and improve memory disturbance before histological amyloid plaque appearance. 4) We found accumulation of Aβ dimer as an initiating factor of amyloid starts in lipid rafts in Tg brains and AD brains, These findings indicate that Aβ accumulation in lipid rafts is an important target for treatment. In lipid rafts, secondary accumulation of AopE and phosphorylated tau were revealed in Tg and AD brains. 5) Administration of melatonin decreases Aβ burden in the Tg brain and improve memory disturbance in Tg. Improve survival rate and oxidative also observed. Clinical application is now planed. 6) Administration of simvastain did not improve Aβ burden in the Tg brain. However, regulation of Aβ generation by cholesterol dependant γ-secretase was possible in lipid raft level. In AopE adjusted 1800 autopsied cohort, high choresterolemia in early adulthood is a risk factor for AD. These findings suggest that treatment of high choresterolemia is protective for onset of AD. Prospective multicenter study, clarification of effects of stains for AD should be studied in cellular and animal model levels.