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The Journal of Neuroscience, March 25, 2009, 29(12):3948-3955; doi:10.1523/JNEUROSCI.5595-08.2009

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Neurobiology of Disease
Interferon-{alpha} Causes Neuronal Dysfunction in Encephalitis

Andrew R. Sas,1 Heather Bimonte-Nelson,3,4 C. Thetford Smothers,1 John Woodward,1 and William R. Tyor1,2

Departments of 1Neurosciences and 2Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina 29425, 3Department of Psychology, Arizona State University, Tempe, Arizona 85287, and 4Arizona Alzheimer's Consortium, Phoenix, Arizona 85006

Correspondence should be addressed to Dr. William R. Tyor, Neurology Service, Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033. Email: william.tyor{at}va.gov

Interferon-{alpha} (IFN{alpha}) is a pleomorphic cytokine produced by nucleated cells in response to viral infection. In patients, treatment with IFN{alpha} has side effects including cognitive impairment resembling subcortical dementia, which is a hallmark of human immunodeficiency virus (HIV)-associated dementia (HAD). IFN{alpha} is increased in the CSF of HAD patients compared with HIV patients without dementia. In this study, blocking IFN{alpha} in a HIV encephalitis (HIVE) mouse model with intraperitoneal injections of IFN{alpha} neutralizing antibodies (NAbs) significantly improved cognitive function compared with untreated or control antibody-treated HIVE mice during water radial arm maze behavioral testing. Treatment with IFN{alpha} NAbs significantly decreased microgliosis and prevented loss of dendritic arborization in the brains of HIVE mice. Furthermore, treatment of primary neuron cultures with IFN{alpha} resulted in dose-dependent loss of dendritic arborization that was blocked with IFN{alpha} NAb treatment and partially blocked with NMDA antagonists [AP5 and MK801 (dizocilpine maleate)] indicating glutamate signaling is involved in IFN{alpha}-mediated neuronal damage. These results show that IFN{alpha} has a major role in the pathogenesis of HIVE in mice and is likely important in the development neurocognitive dysfunction in humans with HIV. Blocking IFN{alpha} could be important in improving cognitive and pathological developments in HAD patients and may be clinically important in other neuroinflammatory diseases as well.

Received Nov. 22, 2008; revised Jan. 6, 2009; accepted Feb. 20, 2009.

Correspondence should be addressed to Dr. William R. Tyor, Neurology Service, Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033. Email: william.tyor{at}va.gov






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