Amyloid β induces microglia to phagocytose neurons via activation of protein kinase Cs and NADPH oxidase. (December 2016)

• Record Type: Journal Article
• Authors: Neniskyte, Urte; Fricker, Michael; Brown, Guy C.
• Is Part Of: International journal of biochemistry & cell biology. Volume 81:Part B(2016)
• Page Start: 346
• Page End: 355
• Publication Date: 2016-12
• Subjects: Aβ amyloid beta -- AEBSF 4-(2-aminoethyl)-benzenesulfonyl fluoride -- cRGD cyclic peptide arginine-glycine-aspartate-d-phenylalanine-valine -- fMLP N-formylmethionyl-leucyl-phenylalanine -- iNOS inducible NO synthase -- LME l-leucine methyl ester -- LPS lipopolysaccharide -- MFG-E8 milk fat globule EGF factor-8 -- NADPH nicotinamide adenine dinucleotide phosphate -- NBT nitro blue tetrazolium -- PHOX phagocyte NADPH oxidase -- PKC protein kinase C -- PMA phorbol 12-myristate 13-acetate -- ROS reactive oxygen species -- SOD1 superoxide dismutase -- TLR toll-like receptor -- TNFα tumour necrosis factor alpha -- VNR vitronectin receptor; Neuroinflammation -- Phagoptosis -- Phagocytosis -- Microglia -- Neurodegeneration; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2016.06.005
• Languages: English
• ISSNs: 1357-2725

Abstract

Graphical abstract: Abstract: Alzheimer's disease is characterized by brain plaques of amyloid beta and by neuronal loss, but it is unclear how amyloid beta causes neuronal loss and how to prevent this loss. We have previously shown that amyloid beta causes neuronal loss by inducing microglia to phagocytose neurons, and here we investigated whether protein kinase Cs and NADPH oxidase were involved in this. The loss of neurons induced by amyloid beta in co-cultures of primary glia and neurons was completely prevented by inhibiting protein kinase Cs with Gö6976 or Gö6983. Directly activating protein kinase Cs with phorbol myristate acetate stimulated microglial phagocytosis, and induced neuronal loss mediated by MFG-E8/vitronectin receptor pathway of microglial phagocytosis. Blocking phagocytosis by MFG-E8 knockout or receptor inhibition left live neurons, indicating microglial phagocytosis was the cause of neuronal death. Phorbol myristate acetate stimulated the microglial NADPH oxidase, and inhibiting the oxidase prevented neuronal loss. A physiological activator of NADPH oxidase, fMLP, also induced neuronal loss dependent on microglia. Amyloid beta-induced neuronal loss was blocked by NADPH oxidase inhibitors, superoxide dismutase or Toll-like receptor function-blocking antibodies. The results indicate that amyloid beta induces microglial phagocytosis of neurons via activating protein kinase Cs and NADPH oxidase, and that activating the kinases or oxidase is sufficient to induce neuronal loss by microglial phagocytosis. Thus inhibiting protein kinase Cs or NADPH oxidase might be beneficial in Alzheimer's disease or other brain pathologies involving inflammatory neuronal loss mediated by microglia.