Department of Biomedicine, Aarhus University, The Skou Building, Høegh-Guldbergs Gade 10, DK-8000, Aarhus C, Denmark.
Max-Delbrueck-Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125, Berlin, Germany.
Nat Commun. 2024 Feb 9;15(1):1224. doi: 10.1038/s41467-024-45627-y.
The peripheral immune system is important in neurodegenerative diseases, both in protecting and inflaming the brain, but the underlying mechanisms remain elusive. Alzheimer's Disease is commonly preceded by a prodromal period. Here, we report the presence of large Aβ aggregates in plasma from patients with mild cognitive impairment (n = 38). The aggregates are associated with low level Alzheimer's Disease-like brain pathology as observed by C-PiB PET and F-FTP PET and lowered CD18-rich monocytes. We characterize complement receptor 4 as a strong binder of amyloids and show Aβ aggregates are preferentially phagocytosed and stimulate lysosomal activity through this receptor in stem cell-derived microglia. KIM127 integrin activation in monocytes promotes size selective phagocytosis of Aβ. Hydrodynamic calculations suggest Aβ aggregates associate with vessel walls of the cortical capillaries. In turn, we hypothesize aggregates may provide an adhesion substrate for recruiting CD18-rich monocytes into the cortex. Our results support a role for complement receptor 4 in regulating amyloid homeostasis.
外周免疫系统在神经退行性疾病中很重要，既能保护又能引发大脑炎症，但潜在机制仍难以捉摸。阿尔茨海默病通常有前驱期。在这里，我们报告了轻度认知障碍患者（n=38）血浆中存在大量 Aβ 聚集体。这些聚集体与通过 C-PiB PET 和 F-FTP PET 观察到的低水平阿尔茨海默病样脑病理学以及 CD18 丰富的单核细胞减少有关。我们将补体受体 4 表征为淀粉样蛋白的强结合物，并表明 Aβ 聚集体通过这种受体在干细胞衍生的小神经胶质细胞中优先被吞噬，并刺激溶酶体活性。单核细胞中 KIM127 整联蛋白的激活促进了 Aβ 的大小选择性吞噬。流体动力学计算表明 Aβ 聚集体与皮质毛细血管壁结合。反过来，我们假设聚集体可能为募集富含 CD18 的单核细胞进入皮质提供粘附基质。我们的结果支持补体受体 4 在调节淀粉样蛋白动态平衡中的作用。
