Defective phagocytosis leads to neurodegeneration through systemic increased innate immune signaling

In 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. To untangle the links between gli...

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Bibliographic Details
Published in:	iScience Vol. 26; no. 10; p. 108052
Main Authors:	Elguero, Johnny E., Liu, Guangmei, Tiemeyer, Katherine, Bandyadka, Shruthi, Gandevia, Heena, Duro, Lauren, Yan, Zhenhao, McCall, Kimberly
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 20-10-2023 Elsevier
Subjects:	Cell biology Immunology Neuroscience Cell biology Neuroscience Immunology
Online Access:	Get full text
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Summary:	In 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. To untangle the links between glial phagocytosis and neurodegeneration, we investigated Drosophila mutants 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 in draper mutants lead to chronic increased immune activation that promotes neurodegeneration. We found that the antimicrobial peptide Attacin-A is highly upregulated in the fat body of aged draper mutants and that the inhibition of the Immune deficiency (Imd) pathway in the glia and fat body of draper mutants led to reduced neurodegeneration. Taken together, these findings indicate that phagocytic defects lead to neurodegeneration via increased immune signaling, both systemically and locally in the brain. [Display omitted] •Loss of Draper phagocytic receptor leads to dysregulation of immune signaling•Draper mutants show the upregulation of AttacinA in the pericerebral fat body•Inhibition of the Imd pathway leads to reduced neurodegeneration in draper mutants•The Imd pathway acts locally in glia and systemically to promote neurodegeneration Neuroscience; Immunology; Cell biology
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally Lead contact
ISSN:	2589-0042 2589-0042
DOI:	10.1016/j.isci.2023.108052