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

1) Tg2576的记忆障碍始于淀粉样斑块出现之前，与脑内乙酰胆碱的选择性降低有关。由于Tg2576几乎再现了阿尔茨海默氏症大脑除神经原纤维缠结外的所有病理改变，因此Tg2576是评估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-1 L286V）表现出Aβ淀粉样蛋白沉积的广泛加速和诱导继发性牛头病。在老年双转基因小鼠中，观察到直小管。3)注射Aβ40和Aβ42抗体可使血浆中Aβ浓度分别升高~ 5倍，提示利用这些特异性抗体进行被动免疫可清除脑内Aβ负荷。这些抗体可以减少Aβ原纤维和Aβ低聚物，并在组织学淀粉样斑块出现之前改善记忆障碍。4)在Tg脑和AD脑的脂筏中，我们发现Aβ二聚体的积累是淀粉样蛋白开始的启动因子，这些发现表明Aβ在脂筏中的积累是治疗的重要靶点。在脂筏中，在Tg和AD的大脑中发现AopE和磷酸化tau的继发性积累。5)给药褪黑素可减少Tg脑内Aβ负荷，改善Tg的记忆障碍。提高了存活率和氧化性。目前正在规划临床应用。6)辛伐他汀未改善Tg大鼠脑内Aβ负荷。然而，在脂筏水平上，胆固醇依赖性γ-分泌酶可能调节Aβ的产生。在AopE调整的1800例尸检队列中，成年早期高舞蹈病胆固醇血症是AD的危险因素。这些发现表明，高舞蹈病胆固醇血症的治疗对阿尔茨海默病的发病具有保护作用。前瞻性多中心研究，阐明染色剂对阿尔茨海默病的作用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.