In the 24 June PNAS Early Edition, researchers report that a biologically ancient defense mechanism for ridding the central nervous system (CNS) of invading pathogens also damages neurons.

Part of the innate immune system, this defense mechanism recognizes lipopolysaccharide (LPS), a component of the outer membrane of certain bacteria. Specific receptors on the surface of microglia bind tightly to LPS, bringing the microbe face-to-face with these macrophage-like cells, which consume invading organisms. However, as revealed by principal author Timothy Vartanian and colleagues at Boston's Beth Israel Deaconess Medical Center, the Children's Hospital, and the Center for Neuroregeneration and Repair at Harvard Medical School, one of these receptors, dubbed Toll-like receptor 4 (TLR4), also initiates a neurodegenerative cascade upon binding LPS.

First author Seija Lehnardt noticed something awry when she added LPS to cultures of mixed cells from rat forebrains. Most cell types, including microglia, oligodendrocytes, and neurons, began to die, the neurons losing axons and dendrites. However, if Lehnardt and colleagues added LPS to pure cultures of neurons, they were unaffected, indicating that other cell types mediated the damage. In support of this hypothesis, the authors found no evidence that LPS could bind directly to neurons.

To prove that the TLR4 receptor mediated this cellular damage, Lehnardt and colleagues repeated their experiments using mixed cell cultures from mice carrying a loss-of-function mutation in the TLR4 gene. In this case, LPS failed to elicit any neuronal damage, though it caused a dramatic loss of axons when added to mixed cells cultured from normal mouse brain.

But what about in vivo? Could LPS be a factor in the neurodegeneration that accompanies such diseases as Alzheimer's and Parkinson's, or in the neuronal losses that follow stroke? To address this question the authors injected LPS or placebo into the brains of young mice suffering from brief hypoxic ischemia. Four of five mice treated with LPS showed signs of axonal damage and neuronal loss in the corpus callosum on the ischemic side of the brain, while the contralateral tissue was undamaged. In contrast, LPS and hypoxic ischemia caused no evident damage in the brains of mice carrying the TLR4 mutation (six animals), while placebo plus ischemia caused no damage in either wild-type or mutant animals.

The results show that activation of the innate immune system may exacerbate the effects of other stresses placed on the central nervous system, particularly oxidative stress, which has long been debated as a central factor in a variety of neurodegenerative disorders including, Alzheimer's (see ARF related news story), Parkinson's (see ARF related story) and Huntington's diseases (see ARF related story).-Tom Fagan.

Reference:
Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9. Epub 2003 Jun 24. Abstract

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References

News Citations

  1. Oxidative Stress Triggers Neuronal Cell-Cycle Reentry
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  3. Disputing the Dismuting—What Is the Real Role of SOD in ALS?

Paper Citations

  1. . Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9. PubMed.

Further Reading

Papers

  1. . Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9. PubMed.

Primary Papers

  1. . Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8514-9. PubMed.