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Abstract：
Impairment of neuronal proteostasis is a hallmark of Alzheimer\'s and other neurodegenerative diseases. However, the underlying molecular mechanisms leading to pathogenic protein aggregation, and the role of secretory chaperone proteins in this process, are poorly understood. We have previously shown that the neural-and endocrine-specific secretory chaperone 7B2 potently blocks in vitro fibrillation of Aβ42. To determine whether 7B2 can function as a chaperone in vivo, we measured plaque formation and performed behavioral assays in 7B2-deficient mice in an hAPPswe/PS1dE9 Alzheimer\'s model mouse background. Surprisingly, immunocytochemical analysis of cortical levels of thioflavin S- and Aβ-reactive plaques showed that APP mice with a partial or complete lack of 7B2 expression exhibited a significantly lower number and burden of thioflavin S-reactive, as well as Aβ-immunoreactive, plaques. However, 7B2 knockout did not affect total brain levels of either soluble or insoluble Aβ. While hAPP model mice performed poorly in the Morris water maze, their brain 7B2 levels did not impact performance. Since 7B2 loss reduced amyloid plaque burden, we conclude that brain 7B2 can impact Aβ disposition in a manner that facilitates plaque formation. These results are reminiscent of prior findings in hAPP model mice lacking the ubiquitous secretory chaperone clusterin.
摘要：
神经元蛋白抑制受损是阿尔茨海默病和其他神经退行性疾病的标志。然而,导致致病蛋白聚集的潜在分子机制，以及分泌伴侣蛋白在这个过程中的作用，知之甚少。我们先前已经表明，神经和内分泌特异性分泌伴侣7B2可有效阻断Aβ42的体外纤颤。为了确定7B2是否可以在体内充当伴侣，我们在hAPPswe/PS1dE9阿尔茨海默病模型小鼠背景下测量了7B2缺陷小鼠的斑块形成并进行了行为测定。令人惊讶的是,对皮质水平的硫黄素S和Aβ反应性斑块的免疫细胞化学分析表明，部分或完全缺乏7B2表达的APP小鼠表现出明显较低的硫黄素S反应性数量和负担，以及Aβ免疫反应性，斑块。然而,7B2敲除不影响可溶性或不溶性Aβ的总脑水平。虽然hAPP模型小鼠在Morris水迷宫中表现不佳，他们的大脑7B2水平并不影响表现。由于7B2损失减少了淀粉样蛋白斑块负荷，我们得出的结论是，大脑7B2可以以促进斑块形成的方式影响Aβ分布。这些结果让人想起缺乏普遍存在的分泌伴侣簇蛋白的hAPP模型小鼠中的先前发现。
