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  • Review Article
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Microglia-mediated neurotoxicity: uncovering the molecular mechanisms

Nature Reviews Neuroscience volume 8, pages 57–69 (2007)Cite this article

Key Points

  • Unregulated microglial activation is a contributing mechanism of neuronal damage in neurodegenerative diseases.

  • Microglia continuously monitor the brain environment and are activated in response to diverse cues, including both endogenous proteins and externally derived environmental toxins.

  • Recent studies show that NADPH oxidase is a common mechanism of microglia-mediated neurotoxicity and is the primary source of microglia-derived extracellular reactive oxygen species (ROS) for numerous neurotoxic stimuli.

  • Pattern recognition receptors are a predominant mechanism through which microglia transduce diverse toxin signals into the production of ROS, identifying a common pathway of microglia-mediated neurotoxicity.

  • By using in vivo imaging to identify deleterious microglial activation combined with targeted anti-inflammatory therapy to inhibit the common neurotoxic mechanisms of microglial activation, it might be possible to slow or halt the progression of neurodegenerative disease.

Abstract

Mounting evidence indicates that microglial activation contributes to neuronal damage in neurodegenerative diseases. Recent studies show that in response to certain environmental toxins and endogenous proteins, microglia can enter an overactivated state and release reactive oxygen species (ROS) that cause neurotoxicity. Pattern recognition receptors expressed on the microglial surface seem to be one of the primary, common pathways by which diverse toxin signals are transduced into ROS production. Overactivated microglia can be detected using imaging techniques and therefore this knowledge offers an opportunity not only for early diagnosis but, importantly, for the development of targeted anti-inflammatory therapies that might slow or halt the progression of neurodegenerative disease.

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Figure 1: Reactive microgliosis drives progressive neurotoxicity.
Figure 2: Microglial PRRs identify neurotoxic and pro-inflammatory ligands.
Figure 3: Intracellular ROS regulate microglial activation.
Figure 4: PET imaging of microglia in neurodegeneration.
Figure 5: Microglial activation, neuronal death and the therapeutic relevance.

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Acknowledgements

L.Z. was supported with a grant from the Michael J. Fox Foundation and the MIUR-FIRB project on Protein Folding and Aggregation: Metal and Biomolecules in Protein Conformational Diseases. M.L.B. was supported by the National Institutes of Health (NIH) Pathway to Independence Award. This work was also supported in part by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH.

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Authors and Affiliations

  1. Neuropharmacology Section, National Institute of Environmental Health Sciences, Research Triangle Park, 27709, North Carolina, USA

    Michelle L. Block & Jau-Shyong Hong

  2. Institute of Biomedical Technologies, Italian National Research Council, Segrate (Milano), 20090, Italy

    Luigi Zecca

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  1. Michelle L. Block
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Correspondence to Michelle L. Block.

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DATABASES

OMIM

Alzheimer's disease

amyotrophic lateral sclerosis

Huntington's disease

multiple sclerosis

Parkinson's disease

Pick's disease

Glossary

Pattern recognition receptors

(PRRs). Receptors that bind to molecular patterns found in pathogens. Examples include the mannose receptor, which binds to terminally mannosylated and polymannosylated compounds, and Toll-like receptors, which are activated by various microbial products such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

Microgliosis

The generalized microglial response to tissue damage that can be either beneficial or detrimental. The negative and progressive response is also referred to as reactive microgliosis.

MPTP

(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). A contamination product from incorrect synthesis of the abused opiate drug, 1-methyl-4-phenyl-4-propionoxypiperidine. In the brain, MPTP is converted to its active metabolite MPP+ (1methyl-4-phenylpyridinium ion), which is selectively toxic to dopaminergic neurons and results in rapid development of Parkinson's disease symptoms in humans and animals.

Lipopolysaccharide

(LPS). An endotoxin that is a complex macromolecule containing a polysaccharide covalently linked to a unique lipid structure, termed lipid A. All gram-negative bacteria synthesize LPS, which is a main constituent of their outer cell membrane.

Endotoxemia

A condition in which endotoxin (a toxin component of the cell wall of gram-negative bacteria that is only released on destruction of the bacterial cell) accesses the blood stream to induce systemic inflammation.

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Block, M., Zecca, L. & Hong, JS. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8, 57–69 (2007). https://doi.org/10.1038/nrn2038

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