Dataset Information

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.

SUBMITTER: Persaud-Sawin DA

PROVIDER: S-EPMC2674560 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Abeta42.

Persaud-Sawin Dixie-Ann DA Banach Lynna L Harry Gaylia Jean GJ

Glia 20090201 3

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 ...[more]

PMID: 18756527

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Project description:Phagocytosis is essential to maintain tissue homeostasis in a large number of inflammatory and autoimmune diseases, but its role in the diseased brain is poorly explored. Recent findings suggest that in the adult hippocampal neurogenic niche, where the excess of newborn cells undergo apoptosis in physiological conditions, phagocytosis is efficiently executed by surveillant, ramified microglia. To test whether microglia are efficient phagocytes in the diseased brain as well, we confronted them with a series of apoptotic challenges and discovered a generalized response. When challenged with excitotoxicity in vitro (via the glutamate agonist NMDA) or inflammation in vivo (via systemic administration of bacterial lipopolysaccharides or by omega 3 fatty acid deficient diets), microglia resorted to different strategies to boost their phagocytic efficiency and compensate for the increased number of apoptotic cells, thus maintaining phagocytosis and apoptosis tightly coupled. Unexpectedly, this coupling was chronically lost in a mouse model of mesial temporal lobe epilepsy (MTLE) as well as in hippocampal tissue resected from individuals with MTLE, a major neurological disorder characterized by seizures, excitotoxicity, and inflammation. Importantly, the loss of phagocytosis/apoptosis coupling correlated with the expression of microglial proinflammatory, epileptogenic cytokines, suggesting its contribution to the pathophysiology of epilepsy. The phagocytic blockade resulted from reduced microglial surveillance and apoptotic cell recognition receptor expression and was not directly mediated by signaling through microglial glutamate receptors. Instead, it was related to the disruption of local ATP microgradients caused by the hyperactivity of the hippocampal network, at least in the acute phase of epilepsy. Finally, the uncoupling led to an accumulation of apoptotic newborn cells in the neurogenic niche that was due not to decreased survival but to delayed cell clearance after seizures. These results demonstrate that the efficiency of microglial phagocytosis critically affects the dynamics of apoptosis and urge to routinely assess the microglial phagocytic efficiency in neurodegenerative disorders.

Dataset Information

Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Abeta42.

Publications

Raft aggregation with specific receptor recruitment is required for microglial phagocytosis of Abeta42.

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