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

1)Tg 2576的记忆障碍在淀粉样斑块出现之前就开始了，并且与脑中乙酰胆碱的选择性减少相关。由于Tg 2576几乎再现了阿尔茨海默氏症脑的所有病理改变，除了神经元缠结，Tg 2576是用于评估乙酰胆碱酯酶抑制剂的作用的优良动物模型。2)双转基因小鼠（Tg 2576 xPS-1 L286 V）显示Aβ淀粉样蛋白沉积广泛加速并诱导继发性tau蛋白病。在老年双转基因小鼠中，观察到直小管。3)注射Aβ40和Aβ42抗体后，血浆Aβ浓度分别升高1.5倍，提示使用这些特异性抗体的被动免疫可清除脑内Aβ负荷。这些抗体可减少Aβ原纤维和Aβ寡聚体，并在组织学淀粉样斑块出现之前改善记忆障碍。4)我们发现Aβ二聚体作为淀粉样蛋白的起始因子在Tg脑和AD脑的脂筏中积聚，这些发现表明Aβ在脂筏中积聚是治疗的重要靶点。在脂筏中，二次积累的AopE和磷酸化的tau蛋白被揭示在Tg和AD脑。5)给予褪黑激素可降低Tg脑中的Aβ负荷，并改善Tg的记忆障碍。提高成活率和氧化也观察到。目前正在计划临床应用。6)辛伐他汀给药未改善Tg脑中的Aβ负荷。胆固醇依赖性γ-分泌酶可能在脂筏水平调节Aβ的生成。在AopE校正的1800例尸检队列中，成年早期的高胆固醇血症是AD的危险因素。这些发现表明，高胆固醇血症的治疗对AD的发作具有保护作用。前瞻性多中心研究，澄清染料对AD的影响应在细胞和动物模型水平上进行研究。

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.