title: Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Abeta42.
abstract: Microglial phagocytosis contributes to the maintenance of brain homeostasis. Mechanisms involved, however, remain unclear. Using Abeta(42) solely as a stimulant, we provide novel insight into regulation of microglial phagocytosis by rafts. We demonstrate the existence of an Abeta(42) threshold level of 250 pg/mL, above which microglial phagocytic function is impaired. Low levels of Abeta(42) facilitate fluorescent bead uptake, whereas phagocytosis is inhibited when Abeta(42) accumulates. We also show that region-specific raft clustering occurs before microglial phagocytosis. Low Abeta(42) levels stimulated this type of raft aggregation, but high Abeta(42) levels inhibited it. Additionally, treatment with high Abeta(42) concentrations caused a redistribution of the raft structural protein flotillin1 from low to higher density fractions along a sucrose gradient. This suggests a loss of raft structural integrity. Certain non-steroidal anti-inflammatory drugs, e.g., the cyclooxygenase 2-specific nonsteroidal anti-inflammatory drugs, celecoxib, raise Abeta(42) levels. We demonstrated that prolonged celecoxib exposure can disrupt rafts in a manner similar to that seen in an elevated Abeta(42) environment: abnormal raft aggregation and Flot1 distribution. This resulted in aberrant receptor recruitment to rafts and impaired receptor-mediated phagocytosis by microglial cells. Specifically, recruitment of the scavenger receptor CD36 to rafts during active phagocytosis was affected. Thus, we propose that maintaining raft integrity is crucial for determining microglial phagocytic outcomes and disease progression.
authors.affiliation: Laboratory of Neurobiology, Neurotoxicology Group, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA. sawind@niehs.nih.gov
authors.forename: Dixie-Ann
authors.initials: DA
authors.lastname: Persaud-Sawin
authors.forename: Lynna
authors.initials: L
authors.lastname: Banach
authors.forename: Gaylia Jean
authors.initials: GJ
authors.lastname: Harry