Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.
Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.
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DOI：
10.1371/journal.pbio.3001358
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发表时间：
2021-09
期刊：
影响因子：
9.8
通讯作者：
Mamo JCL
中科院分区：
文献类型：
--
作者：
Lam V;Takechi R;Hackett MJ;Francis R;Bynevelt M;Celliers LM;Nesbit M;Mamsa S;Arfuso F;Das S;Koentgen F;Hagan M;Codd L;Richardson K;O'Mara B;Scharli RK;Morandeau L;Gauntlett J;Leatherday C;Boucek J;Mamo JCL
一些研究表明，淀粉样β蛋白(A？)的外周代谢与阿尔茨海默病(AD)的风险有关。在血液中，超过90%的Aç以载脂蛋白的形式形成复合体，这增加了脂蛋白介导的轴心对AD风险的可能性。在这项研究中，我们报道了仅在肝脏中合成人Aü的C57BL/6J小鼠(肝细胞特异性人淀粉样蛋白(HSHA)株)的遗传修饰具有显著的神经变性，伴随着毛细血管功能障碍、脂蛋白-A？实质外渗和神经血管炎症。此外，HSHA小鼠在被动回避测试中表现出损害，这表明在海马区依赖的学习中存在损害。透射电子显微镜显示HSHA小鼠明显的神经血管破坏。这项研究为神经退行性变过程的发生和发展提供了脂蛋白-A？/毛细血管轴的因果证据。已有研究表明，淀粉样β蛋白的外周代谢与阿尔茨海默病的风险有关。这项研究表明，人类淀粉样蛋白仅在肝脏中表达，可诱导小鼠出现类似阿尔茨海默病的病理变化，这可能表明阿尔茨海默病的病因学和治疗方法是一条全新的途径。
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. It has been suggested that peripheral metabolism of amyloid-beta is associated with risk for Alzheimer’s disease. This study reveals that the expression of human amyloid exclusively in the liver induces Alzheimer’s disease-like pathologies in mice, potentially indicating a completely novel pathway of Alzheimer’s disease aetiology and therapies.
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影响因子：
23.9
作者：
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通讯作者：
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