Defective phagocytosis leads to neurodegeneration through systemic increased innate immune signaling

Abstract

SummaryIn nervous system development, disease and injury, neurons undergo programmed cell death, leaving behind cell corpses that are removed by phagocytic glia. Altered glial phagocytosis has been implicated in several neurological diseases including Alzheimer’s disease, Parkinson’s disease, and traumatic brain injury. To untangle the links between glial phagocytosis and neurodegeneration, we investigatedDrosophilamutants lacking the phagocytic receptor Draper. Loss of Draper leads to persistent neuronal cell corpses and age-dependent neurodegeneration. Here we investigate whether the phagocytic defects observed indrapermutants lead to chronic increased immune activation that promotes neurodegeneration. A major immune response inDrosophilais the activation of two NFκB signaling pathways that produce antimicrobial peptides, primarily in the fat body. We found that the antimicrobial peptide Attacin-A is highly upregulated in the fat body of ageddrapermutants and that inhibition of the Immune deficiency (Imd) pathway in the glia and fat body ofdrapermutants led to reduced neurodegeneration, indicating that immune activation promotes neurodegeneration indrapermutants. Taken together, these findings indicate that phagocytic defects lead to neurodegeneration via increased immune signaling, both systemically and locally in the brain.