Wilma Friedman, PhD

Inflammation in the brain occurs as a consequence of trauma and in association with numerous neurologic diseases including Alzheimer's disease. Under inflammatory conditions, glial cells produce cytokines, which directly influence neuronal and glial function. Among the effects of inflammatory cytokines is regulation of neurotrophic factor production. Neurotrophic factors critically influence survival and function of many neuronal and glial populations in the central nervous system. The interactions of cytokines and neurotrophic factors in the brain has important consequences for neuronal and glial function during disease.

Work in my lab examines specific cellular mechanisms of cytokine and neurotrophin actions on CNS neurons and glia. We use primary cultures of embryonic neurons to examine mechanisms by which specific cytokines and trophic factors influence neuronal survival. In particular, we investigate the mechanisms governing the influence of neurotrophins on survival of basal forebrain cholinergic neurons, which are among the first to degenerate in Alzheimer's disease. Additionally, we use primary cultures of embryonic glial cells to identify stimuli which regulate production of cytokines and trophic factors, and to determine the consequences of cytokine actions on glial function. Further, we are examining the signaling pathways for specific cytokines in both neurons and glia. We have determined that although certain neuronal and glial populations express the same receptor for the cytokine interleukin-1, the signaling pathways activated by the cytokine are distinct in the different cell types, suggesting that cell type-specific therapeutic strategies may be developed to attenuate CNS inflammation. We are continuing to explore the influence of these cytokines on different CNS cell types. This work is geared to understanding how these factors affect glial and neuronal function, and may ultimately influence neuronal survival, under inflammatory conditions associated with disease in the brain.

Selected Publications:

• Friedman, W.J., Lärkfors, L., Ayer-LeLièvre, C., Ebendal, T., Olson, L., and Persson, H. Regulation of ß-nerve growth factor expression by inflammatory mediators in hippocampal cultures. J. Neurosci. Res. 27: 374-382 (1990).

• Friedman, W.J., Ernfors, P., and Persson, H. In situ hybridization reveals both transient and persistent expression of NT-3/HDNF mRNA in the rat brain during postnatal development. J. Neurosci. 11: 1577-1584 (1991).

• Friedman, W.J., Ibáñez. C.F., Hallböök, F., Persson, H., Cain, L.D., Dreyfus, C.F., and Black, I.B. Differential actions of neurotrophins in the locus coeruleus and basal forebrain. Exp. Neurol. 119: 72-78 (1993).

• Friedman, W.J., Black, I.B., Persson, H., and Ibáñez, C.F. Synergistic trophic actions on basal forebrain neurons revealed by a synthetic NGF/BDNF chimeric molecule. Eur. J. Neurosci. 7: 656-662 (1995).

• Friedman, W.J., Thakur, S., Seidman, L., and Rabson, A.B. Regulation of nerve growth factor mRNA by interleukin-1 in rat hippocampal astrocytes is mediated by NFkB. J. Biol. Chem. 271 (49): 31115-31120 (1996).

• Friedman, W.J., Black, I.B., and Kaplan, D.R. Distribution of BDNF, NT3, and NT4/5 in the rat central nervous system: an immunocytochemical analysis. Neuroscience. 84 (1): 101-114 (1998).

• Farinelli, S.E., Greene, L.A., and Friedman, W.J. Neuroprotective actions of dipyridamole on cultured CNS neurons. J. Neurosci. 18 (14): 5112-5123 (1998).

• Friedman, W.J. Regulation of IL-1 receptor expression in CNS neurons and astrocytes. (Submitted).