Clarification and clinical application of lipoprotein free plasma Aβ

APPsw转基因小鼠连续表达人APP的7倍于野生鼠。8月龄出现神经性斑块，10月龄出现弥漫性斑块。8月龄时，可溶性A-β发生构象变化，变成不溶性A-β。随着抗体在TG脑内的蓄积，GSF和血浆抗体的含量逐渐减少。APPsw TG小鼠出现记忆障碍，乙酰胆碱水平下降，神经元和突触丢失，磷酸化tau积聚。突变型APP的过量生产复制了脑淀粉样变性，提示该小鼠模型是研究阿尔茨海默病发病机制和治疗进展的良好动物模型。APPsw和突变型早老素-1 L286V双转基因小鼠明显加速Aβ淀粉样变性。表达突变型tau R406W的转基因小鼠表现出tau在小鼠脑内的进行性蓄积。然而，这只转tau基因的小鼠并未诱发Aβ淀粉样变性。这些结果表明，Aβ淀粉样变性是阿尔茨海默病病理的基本步骤，因此Aβ淀粉样变性是阿尔茨海默病治疗的最重要的靶点。在散发性阿尔茨海默病患者的血浆中，游离脂蛋白Aβ水平升高。这些发现在阿尔茨海默氏症患者的大脑中也得到了认可。这些发现表明，在阿尔茨海默病患者中，防止Aβ聚集的物理环境受到抑制。我们使用APPsw小鼠，评估了1)Aβ42疫苗，2)褪黑素对脑淀粉样变性的影响。我们还检测了Aβ疫苗在小鼠模型上的副作用。两种候选疗法对APPsw大脑中的一种β淀粉样蛋白都有效。然而，Aβ42疫苗的副作用表明，褪黑素更有可能成为治疗阿尔茨海默病S病的临床试验候选药物。

APPsw transgenic mice continuously expressed 7 times of human APP than that wild mice. Neuritic plaques appeared at 8 months and diffuse plaques appeared at 10 months old. Conformation changes of soluble Aβ into insoluble Aβ occurred at 8 months old. Acceding with Ab accumulation in the Tg brain, the amount of GSF and plasma Ab decreased progressively. Memory disturbance, decreased levels of acetylcholine, neuronal and synaptic loss, accumulation of phosphorylated tau were observed in APPsw Tg mice. Overproduction of mutant APP reproduced brain amylodosis suggesting this mouse model are excellent animal model for studying pathogenesis and development of treatment of Alzheimer's disease.APPsw and mutant presenilin-1 L286V double transgenic mice markedly accelerated Aβ amyloidosis. Transgenic mice expressing mutant tau R406W showed progressive tau accumulation in the mouse brain. However, this tau transgenic mouse did not induce Aβ amyloidosis. These findings indicated that Aβ amyloidosis is the cardinal step of Alzheimer pathology and thus Aβ amylidosis is the most important target of treatment of Alzheimer's disease.In plasma of sporadic Alzheimer's disease, levels of lipoprotein free Aβ were increased. These findings were recognized also in the Alzheimer's brain. These findings suggested that physical circumstance to prevent Aβ aggregation is inhibited in the Alzheimer patients.Using APPsw mice, we evaluated the effects of 1) Aβ42 vaccine, 2) melatonin on brain amyloidosis. We also examined the side effects of Aβ vaccine on the mice model. Both candidate treatments were effective on Aβ amyloid did in the APPsw brain. However, side effects of Aβ42 vaccine suggest that melatonin is the more possible candidate for clinical trial of treatment of Alzheimer 's disease.