Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China; Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China.
Shenzhen Key Laboratory of Marine Bioresources and Ecology, Brain Disease and Big Data Research Institute, College of Life Sciences and Oceanography, Shenzhen University, Shenzhen, China.
Redox Biol. 2024 Apr;70:103064. doi: 10.1016/j.redox.2024.103064. Epub 2024 Feb 1.
Amyloid-beta (Aβ) is a key factor in the onset and progression of Alzheimer's disease (AD). Selenium (Se) compounds show promise in AD treatment. Here, we revealed that selenoprotein K (SELENOK), a selenoprotein involved in immune regulation and potentially related to AD pathology, plays a critical role in microglial immune response, migration, and phagocytosis. In vivo and in vitro studies corroborated that SELENOK deficiency inhibits microglial Aβ phagocytosis, exacerbating cognitive deficits in 5xFAD mice, which are reversed by SELENOK overexpression. Mechanistically, SELENOK is involved in CD36 palmitoylation through DHHC6, regulating CD36 localization to microglial plasma membranes and thus impacting Aβ phagocytosis. CD36 palmitoylation was reduced in the brains of patients and mice with AD. Se supplementation promoted SELENOK expression and CD36 palmitoylation, enhancing microglial Aβ phagocytosis and mitigating AD progression. We have identified the regulatory mechanisms from Se-dependent selenoproteins to Aβ pathology, providing novel insights into potential therapeutic strategies involving Se and selenoproteins.
淀粉样蛋白-β（Aβ）是阿尔茨海默病（AD）发病和进展的关键因素。硒（Se）化合物在 AD 治疗中显示出前景。在这里，我们揭示了参与免疫调节且可能与 AD 病理学有关的硒蛋白 SELENOK 在小胶质细胞免疫反应、迁移和吞噬中发挥关键作用。体内和体外研究证实，SELENOK 缺乏抑制小胶质细胞 Aβ吞噬作用，加剧 5xFAD 小鼠的认知缺陷，而 SELENOK 过表达则逆转了这种缺陷。从机制上讲，SELENOK 通过 DHHC6 参与 CD36 的棕榈酰化，调节 CD36 在小胶质细胞膜上的定位，从而影响 Aβ的吞噬作用。AD 患者和小鼠大脑中的 CD36 棕榈酰化减少。Se 补充促进了 SELENOK 的表达和 CD36 的棕榈酰化，增强了小胶质细胞 Aβ的吞噬作用，减轻了 AD 的进展。我们已经确定了从 Se 依赖性硒蛋白到 Aβ 病理学的调节机制，为涉及 Se 和硒蛋白的潜在治疗策略提供了新的见解。
