Beretta C, Svensson E, Dakhel A, Zyśk M, Hanrieder J, Sehlin D, Michno W, Erlandsson A
Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden.
Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, SE-752 37 Uppsala, Sweden; Department of Neuroinflammation, UCL Queen Square Institute of Neurology, 1 Wakefield Street, WC1N 1PJ London, United Kingdom of Great Britain and Northern Ireland.
Mol Cell Neurosci. 2024 Mar;128:103916. doi: 10.1016/j.mcn.2024.103916. Epub 2024 Jan 19.
Alzheimer's disease (AD) is a neurodegenerative disorder that develops over decades. Glial cells, including astrocytes are tightly connected to the AD pathogenesis, but their impact on disease progression is still unclear. Our previous data show that astrocytes take up large amounts of aggregated amyloid-beta (Aβ) but are unable to successfully degrade the material, which is instead stored intracellularly. The aim of the present study was to analyze the astrocytic Aβ deposits composition in detail in order to understand their role in AD propagation. For this purpose, human induced pluripotent cell (hiPSC)-derived astrocytes were exposed to sonicated Aβ fibrils and magnetic beads. Live cell imaging and immunocytochemistry confirmed that the ingested Aβ aggregates and beads were transported to the same lysosomal compartments in the perinuclear region, which allowed us to successfully isolate the Aβ deposits from the astrocytes. Using a battery of experimental techniques, including mass spectrometry, western blot, ELISA and electron microscopy we demonstrate that human astrocytes truncate and pack the Aβ aggregates in a way that makes them highly resistant. Moreover, the astrocytes release specifically truncated forms of Aβ via different routes and thereby expose neighboring cells to pathogenic proteins. Taken together, our study establishes a role for astrocytes in mediating Aβ pathology, which could be of relevance for identifying novel treatment targets for AD.
阿尔茨海默病（AD）是一种历经数十年发展的神经退行性疾病。包括星形胶质细胞在内的神经胶质细胞与AD发病机制紧密相关，但其对疾病进展的影响仍不明确。我们之前的数据表明，星形胶质细胞会摄取大量聚集的淀粉样β蛋白（Aβ），但无法成功降解这些物质，而是将其储存在细胞内。本研究的目的是详细分析星形胶质细胞内Aβ沉积物的组成，以了解它们在AD传播中的作用。为此，将人诱导多能干细胞（hiPSC）衍生的星形胶质细胞暴露于经超声处理的Aβ纤维和磁珠。活细胞成像和免疫细胞化学证实，摄入的Aβ聚集体和磁珠被转运至核周区域的相同溶酶体区室，这使我们能够成功地从星形胶质细胞中分离出Aβ沉积物。通过一系列实验技术，包括质谱分析、蛋白质印迹法、酶联免疫吸附测定和电子显微镜，我们证明人星形胶质细胞以一种使其具有高度抗性的方式截短并包裹Aβ聚集体。此外，星形胶质细胞通过不同途径释放特定截短形式的Aβ，从而使邻近细胞暴露于致病蛋白。综上所述，我们的研究确定了星形胶质细胞在介导Aβ病理过程中的作用，这可能与确定AD的新治疗靶点相关。
