The peripheral immune system has emerged as a regulator of neurodegenerative diseases such as Alzheimer’s disease.Microglia are resident immune cells in the brain that may orchestrate communication between the centra...The peripheral immune system has emerged as a regulator of neurodegenerative diseases such as Alzheimer’s disease.Microglia are resident immune cells in the brain that may orchestrate communication between the central nervous system and peripheral immune system,though the mechanisms are unclear.Here,we found that gamma-type immunoglobulin,a product originating from peripheral blood B cells,localized in the brain parenchyma of multiple mouse models with amyloid pathology,and was enriched on microglia but not on other brain cell types.Further experiments showed that gamma-type immunoglobulin bound to microglial cell membranes and led to diverse transcriptomic changes,including upregulation of pathways related to phagocytosis and immunity.Functional assays demonstrated that gamma-type immunoglobulin enhanced microglial phagocytic capacity for amyloid-beta fibrils via its Fc fragment,but not Fab fragment,fragment.Our data indicate that microglia,when exposed to gamma-type immunoglobulin,exhibit an enhanced capacity for clearing amyloid-beta fibrils,potentially via the gamma-type immunoglobulin Fc fragment signaling pathway.This suggests that parenchymal gamma-type immunoglobulin should be further investigated to determine whether it may play a beneficial role against Alzheimer’s disease by enhancing microglial function.展开更多
基金supported by the National Natural Science Foundation of China,Nos.82171082(to ZX),32000727(to TZ),32370731(to YZ)Guangdong Basic and Applied Basic Research Foundation,No.2024A151501069(to ZX)+1 种基金Shenzhen Science and Technology Program,Nos.JCYJ20210324101603009(to ZX),GJHZ20220913142807015(to TZ),JCYJ20220531100204010(to TZ),JCYJ20230807091308018(to YZ)Shenzhen Medical Research Funds,No.A2303068(to TZ).
文摘The peripheral immune system has emerged as a regulator of neurodegenerative diseases such as Alzheimer’s disease.Microglia are resident immune cells in the brain that may orchestrate communication between the central nervous system and peripheral immune system,though the mechanisms are unclear.Here,we found that gamma-type immunoglobulin,a product originating from peripheral blood B cells,localized in the brain parenchyma of multiple mouse models with amyloid pathology,and was enriched on microglia but not on other brain cell types.Further experiments showed that gamma-type immunoglobulin bound to microglial cell membranes and led to diverse transcriptomic changes,including upregulation of pathways related to phagocytosis and immunity.Functional assays demonstrated that gamma-type immunoglobulin enhanced microglial phagocytic capacity for amyloid-beta fibrils via its Fc fragment,but not Fab fragment,fragment.Our data indicate that microglia,when exposed to gamma-type immunoglobulin,exhibit an enhanced capacity for clearing amyloid-beta fibrils,potentially via the gamma-type immunoglobulin Fc fragment signaling pathway.This suggests that parenchymal gamma-type immunoglobulin should be further investigated to determine whether it may play a beneficial role against Alzheimer’s disease by enhancing microglial function.
