SELENOK-dependent CD36 palmitoylation regulates microglial functions and Aβ phagocytosis
Pei Ouyang,
Zhiyu Cai,
Jiaying Peng,
Shujing Lin,
Xiaochun Chen,
Changbin Chen,
Ziqi Feng,
Lin Wang,
Guoli Song,
Zhonghao Zhang
Affiliations
Pei Ouyang
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
Zhiyu Cai
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
Jiaying Peng
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
Shujing Lin
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
Xiaochun Chen
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
Changbin Chen
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
Ziqi Feng
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
Lin Wang
College of Biology and Food Engineering, Anyang Institute of Technology, Anyang, China
Guoli Song
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; Corresponding author. 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.
Zhonghao Zhang
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; Corresponding author. 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.
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.
