Department of Neurobiology, KI-Alzheimer's Disease Research Center, Care Sciences and Society, Karolinska Institutet, Huddinge, Sweden.
EMBO Mol Med. 2012 Oct;4(10):1097-111. doi: 10.1002/emmm.201201462. Epub 2012 Aug 30.
Thioredoxin-1 (Trx1) is an endogenous dithiol reductant and antioxidant that was shown to be decreased in Alzheimer's disease (AD) neurons. A truncated form of Trx1, thioredoxin 80 (Trx80), was reported to be secreted from monocytes having cytokine activity. Here, we show that Trx80 is present in human brain in an aggregated form. Trx80 localizes mainly to neurons and is dramatically decreased in AD brains. Trx80 levels in cerebrospinal fluid (CSF) correlate with those of the classical AD biomarkers amyloid-β (Aβ) 1-42 and total tau. Moreover, Trx80 measurements in CSF discriminate between patients with stable mild cognitive impairment, prodomal AD and mild AD. We report that ADAM10 and 17, two α-secretases processing the Aβ precursor protein, are responsible for Trx80 generation. In contrast to the periphery, Trx80 has no pro-inflammatory effects in glia, either by itself or in combination with Aβ or apolipoprotein E. Instead, Trx80 inhibits Aβ(1-42) aggregation and protects against its toxicity. Thus, a reduction in Trx80 production would result in increased Aβ polymerization and enhanced neuronal vulnerability. Our data suggest that a deficit in Trx80 could participate in AD pathogenesis.
硫氧还蛋白-1（Trx1）是一种内源性二硫醇还原剂和抗氧化剂，其在阿尔茨海默病（AD）神经元中减少。据报道，Trx1 的一种截断形式，即硫氧还蛋白 80（Trx80），从具有细胞因子活性的单核细胞中分泌。在这里，我们表明 Trx80 以聚集的形式存在于人脑。Trx80 主要定位于神经元，并在 AD 脑中显著减少。脑脊液（CSF）中的 Trx80 水平与经典 AD 生物标志物淀粉样蛋白-β（Aβ）1-42 和总tau 相关。此外，CSF 中的 Trx80 测量可区分稳定轻度认知障碍、前驱 AD 和轻度 AD 患者。我们报告说，ADAM10 和 17，两种切割 Aβ 前体蛋白的α-分泌酶，负责 Trx80 的产生。与外周组织不同，Trx80 本身或与 Aβ 或载脂蛋白 E 结合时，对神经胶质细胞没有促炎作用。相反，Trx80 抑制 Aβ（1-42）聚集并防止其毒性。因此，Trx80 产生减少会导致 Aβ 聚合增加和神经元易损性增强。我们的数据表明，Trx80 的缺乏可能参与 AD 的发病机制。
