Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

中文翻译：

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在阿尔茨海默病小鼠模型中，应激诱导型磷蛋白 1 水平的增加会加速淀粉样蛋白 β 的沉积。

分子伴侣和辅助伴侣是蛋白质质量控​​制机制的一部分，已被证明可以通过多种方式调节阿尔茨海默病 (AD) 病理学的不同方面。值得注意的是，辅助伴侣 STI1 在 AD 中表现出水平升高，可以在体外保护哺乳动物神经元免受淀粉样蛋白-β 毒性的影响，而 STI1 水平降低会加剧秀丽隐杆线虫中的 Aβ 毒性。然而，增加STI1水平是否可以保护体内神经元仍然未知。我们确定 STI1 和/或 Hsp90 的过度表达可以保护表达 Aβ(3-42) 的线虫免受 Aβ 介导的麻痹。在体外，哺乳动物神经元也受到内源性 STI1 水平升高的保护，这种作用主要是由于细胞外 STI1。令人惊讶的是，在 AD 的 5xFAD 小鼠模型中，通过过度表达 STI1，我们发现淀粉样蛋白负荷增加，从而放大了这些突变体的神经毒性并加剧了空间记忆缺陷。STI1 水平的升高扰乱了 Aβ 调节酶（BACE1 和 MMP-2）的表达，这表明小鼠中淀粉样蛋白负荷增加的潜在机制。值得注意的是，我们观察到 STI1 在 5xFAD 小鼠和人脑组织的致密核心 AD 斑块中积累。我们的研究结果表明，STI1 水平升高有助于 Aβ 积累，并且 STI1 沉积在小鼠和人类的 AD 斑块中。我们的结论是，尽管 STI1 对秀丽隐杆线虫和哺乳动物培养的神经元具有保护作用，但在体内，STI1 升高的主要作用对 AD 是有害的。