In age-related neurodegenerative disease, like Alzheimer’s and Parkinson’s disease, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm- and human cell models for disease. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated SERF2 brain-specific knockout mice which, unlike full body knockout mice, were viable, and showed no major behavioral and cognitive abnormalities. We combined these knockout mice with the APPPS1 mouse model for human amyloid beta aggregation. Using structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in human brain, we show that knockout of SERF2 alters the structure of amyloid fibrils and deposits. Moreover, scanning transmission electron microscopy revealed thicker, shorter and more densely packed amyloid in absence of SERF2. Altogether, our data reveal pleiotropic functions of SERF in development and aging and support a function as a modifier of amyloid aggregation in mammalian brain. Our results indicate that single cellular factors like SERF can determine the structural outcome of amyloid aggregation, offering possibilities for polymorphism-based disease interventions.

中文翻译：

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SERF缺失改变了阿尔茨海默病小鼠模型中的淀粉样蛋白聚集

在与年龄相关的神经退行性疾病中，如阿尔茨海默病和帕金森病，疾病特异性蛋白质变得易于聚集并形成淀粉样蛋白样沉积物。SERF蛋白的消耗改善了蠕虫和人类疾病细胞模型中的这种毒性过程。然而，SERF 是否会改变哺乳动物大脑中的淀粉样蛋白病理学仍然未知。在这里，我们生成了 SERF2 大脑特异性基因敲除小鼠，与全身基因敲除小鼠不同，这些小鼠是可行的，并且没有表现出重大的行为和认知异常。我们将这些基因敲除小鼠与 APPPS1 小鼠模型结合起来进行人淀粉样蛋白 β 聚集。使用以前用于区分人脑中淀粉样蛋白多态性的结构特异性淀粉样蛋白染料，我们表明 SERF2 的敲除会改变淀粉样蛋白原纤维和沉积物的结构。而且，扫描透射电子显微镜显示在没有 SERF2 的情况下更厚、更短和更密集的淀粉样蛋白。总之，我们的数据揭示了 SERF 在发育和衰老中的多效性，并支持作为哺乳动物大脑中淀粉样蛋白聚集调节剂的功能。我们的结果表明，像 SERF 这样的单细胞因子可以决定淀粉样蛋白聚集的结构结果，为基于多态性的疾病干预提供了可能性。