Development and clinical application of novel methods for diagnosis and therapy of Alzheimer disease by regulation of neurotoxic oligomer

近年来的研究表明，低聚物是引起包括阿尔茨海默病在内的痴呆患者突触和神经元紊乱的直接病原体。在本研究中，我们建立了针对Ass、tau和α-突触核蛋白的特异性抗体，建立了ELISA和检测系统，在AD患者的大脑和脑脊液中发现了可溶性低聚物、天然存在的抗Ass抗体。建立DLB （TgSNY）和AD （2xTgTau+/- app +/-）模型小鼠。利用微阵列技术阐明了2xTgTau+/- app +/-和NFT形成的Ass诱导的tau病变的病理级联以及神经元细胞死亡。许多生物学途径参与了这些最终级联反应。抗牛磺酸抗体可降低小鼠脑内牛磺酸负荷和低聚物含量，增加脑脊液和血浆中牛磺酸单体含量。因此，抗低聚物治疗是治疗神经退行性痴呆的一种可能的药物。

Recent studies suggest that oligomers are direct pathogenic agents to cause synaptic and neuronal disturbance in dementia patients including Alzheimer's disease. In this study, we established special antibodies to Ass, tau and α-synuclein to develop ELISA and detection systems, showing soluble oligomers, naturally occurred anti-Ass antibodies in brains and CSF in AD patients. Model mice of DLB (TgSNY) and AD (2xTgTau+/-APP+/-) were established. The pathological cascades of Ass induced tauopathy using 2xTgTau+/-APP+/- and NFT formation and neuronal cell deaths using by micro arrays were elucidated. Many biological pathways involved in these final cascades. Administration of anti-Ass antibodies reduced Ass burden and Ass oligomer in mice brains and increased in Ass monomer in CSF and plasma. Thus, anti-oligomer therapy is a possible agent for cure of neurodegenerative dementia.