Clarification and clinical application of lipoprotein free plasma Aβ

APPsw转基因小鼠持续表达人APP的量是野生型小鼠的7倍。神经炎性斑块出现在8个月龄，弥漫性斑块出现在10个月龄。8月龄时，可溶性Aβ构象开始转变为不溶性Aβ。随着Tg脑内Ab的蓄积，GSF和血浆Ab的量进行性下降。在APPsw Tg小鼠中观察到记忆障碍、乙酰胆碱水平降低、神经元和突触丢失、磷酸化tau蛋白蓄积。突变型APP的过量产生可复制脑淀粉样变性，提示该小鼠模型是研究阿尔茨海默病发病机制和开发治疗的良好动物模型，APPsw和突变型早老素-1 L286 V双转基因小鼠明显加速Aβ淀粉样变性。表达突变体tau R406 W的转基因小鼠在小鼠脑中显示进行性tau积累。然而，这种tau转基因小鼠没有诱导Aβ淀粉样变性。提示Aβ淀粉样变是Alzheimer病的重要病理基础，Aβ淀粉样变是治疗Alzheimer病的重要靶点。这些发现在阿尔茨海默氏症的大脑中也得到了认可。本研究以APPsw小鼠为研究对象，观察了1）Aβ42疫苗、2）褪黑素对脑淀粉样变性的影响。我们还检查了Aβ疫苗对小鼠模型的副作用。两种候选治疗对APPsw脑中的Aβ淀粉样蛋白均有效。然而，Aβ42疫苗的副作用表明，褪黑激素是治疗阿尔茨海默病的临床试验的更可能的候选者。

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.