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Mol Neurobiol. 2010 Jun;41(2-3):242-7. doi: 10.1007/s12035-010-8105-9. Epub 2010 Mar 2.

Inflammatory neurodegeneration and mechanisms of microglial killing of neurons.

Author information

1
Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK. gcb@mole.bio.cam.ac.uk

Abstract

Inflammatory neurodegeneration contributes to a wide variety of brain pathologies. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include: (1) acute activation of the phagocyte NADPH oxidase (PHOX) found in microglia, (2) expression of the inducible nitric oxide synthase (iNOS) in glia, and (3) microglial phagocytosis of neurons. Activation of PHOX (by cytokines, beta-amyloid, prion protein, lipopolysaccharide, ATP, or arachidonate) causes microglial proliferation and inflammatory activation; thus, PHOX is a key regulator of inflammation. However, activation of PHOX alone causes little or no death, but when combined with iNOS expression results in apparent apoptosis via peroxynitrite production. Nitric oxide (NO) from iNOS expression also strongly synergizes with hypoxia to induce neuronal death because NO inhibits cytochrome oxidase in competition with oxygen, resulting in glutamate release and excitotoxicity. Finally, microglial phagocytosis of these stressed neurons may contribute to their loss.

PMID:
20195798
DOI:
10.1007/s12035-010-8105-9
[Indexed for MEDLINE]

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