Inflammation in the central nervous system is often accompanied by complement activation and the complement system has been implicated in diverse disorders such as Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. We have utilized the cuprizone model of demyelination-remyelination and show that complement is a negative factor during demyelination, however lack of an intact complement system significantly delays remyelination. There is decreased expression of the protective Crry protein during demyelination and a CNS specific soluble Crry protein completely inhibits demyelination. These results indicate that complement is active even in CNS diseases without antibody involvement (as is the case in the cuprizone model). In order to further delineate the role of complement in neuroinflammation we propose to test the following hypotheses: (1) The production of anaphylatoxin proteins plays a key role in demyelination through increased microglial activation, but these inflammatory proteins are required for microglial activation required for myelin clearance. Both C3a and C5a are produced during complement activation, yet it is very difficult to dissect the roles these proteins, either alone or in combination. We have generated novel viral constructs (adenoviral and lentiviral) for CNS delivery and we have mice with genetic deletions in the receptors for these proteins that we can use to test our hypothesis. (2) Loss of Crry expression creates an environment in the corpus callosum that facilitates complement activation; yet decreased complement activation leads to loss of myelin clearance and remyelination delay. Our preliminary data have shown significant loss of Crry protein in cuprizone-treated mice and CNS production of a soluble Crry protein prevents demyelination. Surprisingly, when cuprizone is removed from the diet sCrry transgenic mice undergo demyelination when they should be remyelinating. These data show that primary demyelination can be prevented, but there is an adverse affect on remyelination with complement blockade. We will use virally delivered soluble Crry protein to test the ability of the protein to alter local demyelination and remyelination in this system. Our studies will begin to uncover how disparate complement proteins interact in the CNS to mediate different effector functions, information that will be critical for understanding how and when complement might be a candidate therapeutic target in disease. There are a number of diseases that are characterized by complement activation in the CNS including Alzheimer's disease, amyotrophic lateral sclerosis and multiple sclerosis. We are using a mouse model of demyelination and remyelination to study the role of immune complement in the effector stage of disease. Our unique model also allows us to study the most critical aspect of myelin biology in the human, namely the remyelination process. ? ? ?

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Neural Degenerative Disorders and Glial Biology Study Section (NDGB)
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Utz, Ursula
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Iowa Cancer Research Foundation, Inc.
United States
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Fraczek, Laura A; Martin, Carol B; Martin, Brian K (2011) c-Jun and c-Fos regulate the complement factor H promoter in murine astrocytes. Mol Immunol 49:201-10
Ingersoll, Sarah A; Martin, Carol B; Barnum, Scott R et al. (2010) CNS-specific expression of C3a and C5a exacerbate demyelination severity in the cuprizone model. Mol Immunol 48:219-30