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Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.
PLOS Biology ( IF 7.8 ) Pub Date : 2021-09-14 , DOI: 10.1371/journal.pbio.3001358
Virginie Lam 1, 2 , Ryusuke Takechi 1, 2 , Mark J Hackett 1, 3 , Roslyn Francis 4, 5 , Michael Bynevelt 6 , Liesl M Celliers 4, 7 , Michael Nesbit 1, 2 , Somayra Mamsa 1 , Frank Arfuso 1 , Sukanya Das 1 , Frank Koentgen 8 , Maree Hagan 8 , Lincoln Codd 9 , Kirsty Richardson 10 , Brenton O'Mara 4 , Rainer K Scharli 11, 12 , Laurence Morandeau 11, 12 , Jonathan Gauntlett 8 , Christopher Leatherday 13 , Jan Boucek 13 , John C L Mamo 1, 2
Affiliation  

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

中文翻译:

仅限于肝脏的人类淀粉样蛋白的合成会导致类似阿尔茨海默病的神经退行性表型。

多项研究表明,淀粉样蛋白 β (Aß) 的外周代谢与阿尔茨海默病 (AD) 的风险相关。在血液中,超过 90% 的 Aß 复合为载脂蛋白,这增加了脂蛋白介导轴导致 AD 风险的可能性。在这项研究中,我们报告了 C57BL/6J 小鼠的基因改造仅在肝脏(肝细胞特异性人淀粉样蛋白 (HSHA) 菌株)中合成人类 Aß 的基因修饰具有显着的神经变性,伴随毛细血管功能障碍、脂蛋白 Aß 的实质外渗和神经血管炎。此外,HSHA 小鼠在被动回避测试中表现出受损,表明海马依赖性学习受损。透射电子显微镜显示 HSHA 小鼠有明显的神经血管破坏。
更新日期:2021-09-14
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