PT -期刊文章盟Tatsuo马诺AU - Takashi野中郁次郎盟Airi Tarutani AU - Tadafumi桥本AU - Shigeo Murayama盟Masato长谷川AU - Iwatsubo武盟Atsushi岩田聪TI - Tau-related BRCA1的障碍导致阿尔茨海默病神经可塑性降低(P2.191) DP - 2018年4月10 TA -神经病学PG - P2.191 VI - 90 IP - 15补充4099 - //www.ez-admanager.com/content/90/15_Supplement/P2.191.short 4100 - http://n.neurolog首页y.org/content/90/15_Supplement/P2.191.full所以Neurology2018 4月10;90 AB -目的:本研究的目的是阐明BRCA1功能障碍的机理及其生物相关性的广告。背景:在之前的研究中,我们演示了BRCA1障碍在阿尔茨海默病(AD)通过特异性神经元methylome的筛选过程分析。BRCA1基因是主要的DNA修复蛋白之一。在广告的大脑,mislocalized神经元细胞的细胞质也insolubilized。设计/方法:淀粉样β的影响(Aβ)DNA损伤并使用N2a细胞系BRCA1的表达进行了分析。DNA损伤是由彗星量化分析(单细胞凝胶电泳)尾部DNA百分比。在seed-dependentτ聚合模型,介绍了人类τcDNA和重组τ须根SH-SY5Y细胞系。分析BRCA1在体内的功能,与BRCA1 shRNA慢病毒注入的齿状回APP / PS1老鼠。结果:βtreatment N2a细胞浓度的方式BRCA1的表达增加,和BRCA1混战诱导DNA损伤的积累和减少neurite-like过程形成的细胞系。 BRCA1 shifted to insoluble fraction upon tau aggregation in SH-SY5Y cells and co-localized with cytoplasmic tau. These data suggested that BRCA1 is supposed to fix Aβ-induced DNA damage, however, tau-associated BRCA1 dysfunction resulted in the accumulation of DNA damage leading to reduced neuronal plasticity. To confirm these phenomena in vivo, we analyzed APP/PS1 and 3xTg-AD mice. BRCA1 stayed in soluble fraction in APP/PS1 mice and its knock-down resulted in increased DNA damage and reduced synapse density. In 3xTg-AD mice, BRCA1 became insolubilized and mislocalized to the cytoplasm, resulted in the increase of DNA damage in an age-dependent manner.Conclusions: We demonstrated that Aβ induced DNA damage, which was repaired by BRCA1 when aggregated tau was absent. However, tau aggregation sequesters BRCA1 and impairs its function, which increases DNA damages, also leading to reduced neuronal plasticity.Disclosure: Dr. Mano has nothing to disclose. Dr. Nonaka has nothing to disclose. Dr. Tarutani has nothing to disclose. Dr. Hashimoto has nothing to disclose. Dr. Murayama has nothing to disclose. Dr. Hasegawa has nothing to disclose. Dr. Iwatsubo has nothing to disclose. Dr. Iwata has nothing to disclose.

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