Megf10 Is a Receptor for C1Q That Mediates Clearance of Apoptotic Cells by Astrocytes.

UNLABELLED: Multiple EGF-like domains 10 (Megf10) is a class F scavenger receptor (SR-F3) expressed on astrocytes and myosatellite cells, and recessive mutations in humans result in early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD). Here we report that Megf10-deficient mice have increased apoptotic cells in the developing cerebellum and have impaired phagocytosis of apoptotic cells by astrocytes ex vivo We also report that cells transfected with Megf10 gain the ability to phagocytose apoptotic neurons and that Megf10 binds with high affinity to C1q, an eat-me signal for apoptotic cells. In contrast, cells expressing Megf10 with EMARDD mutations have impaired apoptotic cell clearance and impaired binding to C1q. Our studies reveal that Megf10 is a receptor for C1q and identify a novel role for Megf10 in clearance of apoptotic cells in the mammalian developing brain with potential relevance to EMARDD patients and other CNS disorders. SIGNIFICANCE STATEMENT: Apoptosis is a universal homeostatic process and occurs in many disease conditions. Multiple EGF-like domains 10 (Megf10) is emerging as an essential receptor for synaptic pruning, clearance of neuronal debris, and for muscle differentiation. Here we define a novel Megf10-dependent pathway for apoptotic cell clearance and show that Megf10 is a receptor for C1q, an eat-me signal, that binds phosphatidylserine expressed on the surface of apoptotic cells. Understanding the pathways by which apoptotic cells are cleared in the CNS is relevant to many physiological and pathological conditions of the CNS.

Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal ß-Amyloid Clearance Pathways and Slows Progression of Alzheimer's Like-Disease in PS1-APP Mice.

CX3CR1 is a chemokine receptor expressed on microglia that binds Fractalkine (CX3CL1) and regulates microglial recruitment to sites of neuroinflammation. Full deletion of CX3CR1 in mouse models of Alzheimer's disease have opposing effects on amyloid-ß and tau pathologies raising concerns about the benefits of targeting CX3CR1 for treatment of this disease. Since most therapies achieve only partial blockade of their targets, we investigated the effects of partial CX3CR1 deficiency on the development and progression of amyloid-ß deposition in the PS1-APP Alzheimer's mouse model. We generated PS1-APP mice heterozygous for CX3CR1 (PS1-APP-CX3CR1+/-) and analyzed these mice for Alzheimer's-like pathology. We found that partial CX3CR1 deficiency was associated with a significant reduction in Aß levels and in senile-like plaque load in the brain as compared with age-matched PS1-APP mice. Reduced Aß level in the brain was associated with improved cognitive function. Levels of the neuronal-expressed Aß-degrading enzymes insulysin and matrix metalloproteinase 9, which are reduced in the brains of regular PS1-APP mice, were significantly higher in PS1-APP-CX3CR1+/- mice. Our data indicate that lowering CX3CR1 levels or partially inhibiting its activity in the brain may be a therapeutic strategy to increase neuronal Aß clearance, reduce Aß levels and delay progression of Alzheimer's-Like disease. Our findings also suggest a novel pathway where microglial CX3CR1 can regulates gene expression in neurons.