Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, United States of America; Department of Health and Exercise Science, Center for Healthy Aging, Colorado State University (Current), Fort Collins, CO, United States of America.
Department of Integrative Physiology, University of Colorado Boulder, Boulder, CO, United States of America; Department of Health and Exercise Science, Center for Healthy Aging, Colorado State University (Current), Fort Collins, CO, United States of America.
Neurobiol Dis. 2021 Nov;159:105493. doi: 10.1016/j.nbd.2021.105493. Epub 2021 Aug 28.
The amyloid beta (Aβ) peptide is believed to play a central role in Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily selected functions of Aβ are incompletely understood. Here, we report that nanomolar concentrations of Aβ act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that Aβ can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by Aβ have a transcriptional signature similar to neurotoxic "A1" astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of Aβ at low concentrations is distinct from the transcriptome changes induced by the high/supraphysiological doses of Aβ often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for Aβ and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.
淀粉样蛋白 β（Aβ）肽被认为在阿尔茨海默病（AD）中发挥核心作用，AD 是最常见的与年龄相关的神经退行性疾病。然而，Aβ 的自然、进化选择功能尚未完全了解。在这里，我们报告称，纳摩尔浓度的 Aβ 与已知细胞因子协同作用，促进原代人星形胶质细胞（一种越来越多与大脑衰老和 AD 相关的细胞类型）的促炎激活。通过转录组学（RNA-seq），我们表明 Aβ 可以在先前显示诱导星形胶质细胞免疫激活的细胞因子混合物中直接替代补体成分 C1q。此外，我们表明，Aβ 协同激活的星形胶质细胞具有与随着年龄增长和 AD 中积累的神经毒性“A1”星形胶质细胞相似的转录特征。有趣的是，我们发现 Aβ 在低浓度下的这种生物学作用与体外研究中常用的高/超生理剂量 Aβ 诱导的转录组变化不同。总的来说，我们的结果表明 Aβ 具有重要的细胞因子样功能，以及它可能直接导致与大脑衰老和 AD 相关的神经炎症的新机制。
