Glial fibrillary acidic protein (GFAP) and neuronal sprouting

Astrocytes are the most abundant type of neuroglia, and are important in supporting normal neuronal function in the brain. Their activation is a prominent feature in the brain in response to injury and during normal aging. This thesis considers an upstream role of astrocytes, particularly the expression of the astrocyte-specific glial fibrillary acidic protein (GFAP), in neuronal changes during injury and aging.; The first part of this thesis examined how 17beta-estradiol (E2) exerts its beneficial role on neurons. Neuronal remodeling in response to deafferenting lesion in the brain can be enhanced by E2. Astrocytes are among the targets of E2 action. E2 inhibits GFAP expression and enhances compensatory sprouting after entorhinal cortex lesion in rats, which models the hippocampal deafferentation of Alzheimer's disease. We also used an in vitro lesion model based on astrocyte-neuron co-culture to exam the role of E2 on neurite sprouting. We showed that effects of E2 are mediated by the transcriptional repression of GFAP.; We further tested the hypothesis that increased GFAP expression in response to injury and during aging is a proximal cause of impaired neurite outgrowth. Aging astrocytes do not respond to E2 in facilitating post-lesion remodeling. Knockdown of astrocytic GFAP reverses this age-related impairment. Furthermore, in the intact astrocyte-neuron co-culture, aging astrocytes support less neurite outgrowth, which may model the neuron atrophy occurs during normal aging. Experimental lowering of GFAP by RNA interference alleviates this aging phenotype. Moreover, modulation of GFAP expression led to increased expression and reorganization of astrocytic laminin. The astrocytic process-associated laminin array is a favorable substrate for neurite outgrowth.; Mechanism of oxidative stress (OS) may underline age-related changes in the brain. We considered the potential role of OS on GFAP expression and tried to identify transcription factor(s) involved in these processes. The ∼1.9 kb 5'-flanking rat Gfap promoter region is sufficient for OS- and age-related regulation of GFAP. Further analysis indicated the involvement of NF1-like protein(s), but not NF-kappaB, in regulating the transcriptional response of GFAP to OS.