What is the role of GFAP in the healthy and injured brain?

Glial fibrillary acidic protein (GFAP) is an intermediate filament expressed in most astrocytes in the healthy rat and human brain. GFAP is markedly upregulated in astrocytes after acute brain injury or in neurological disease and is widely used as an indicator of astrocyte reactivity. Given this reliable increase, it appears that GFAP is an integral part of the brain’s response to neurological disease and trauma. Yet despite the independent development of 3 GFAP KO mouse lines more than 10 years ago, only speculation has ensued regarding GFAP’s protective and structural support function in the healthy and injured brain.

GFAP expression is variable in different CNS regions in the healthy adult brain. In the healthy mouse forebrain, GFAP is expressed in cortical layer I astrocytes, which form the glia limitans along the meninges; in white matter astrocytes; and in astrocyte endfeet, which contact and completely cover the vasculature in cortical gray matter. Mice lacking GFAP develop normally, though Liedtke et al. observed signs of neurodegeneration in GFAP KO mice after 6 months, including poorly vascularized and disorganized white matter, late onset demyelination after 12 months and increased permeability of the blood-brain barrier (BBB). These findings suggest that GFAP expression is essential for long-term health of these brain structures.

The presence of GFAP along blood vessels and within white matter tracts, both anatomical structures particularly vulnerable to mechanical shear stress, might point toward a structural support function of this cytoskeletal protein. Nawashiro et al., provided experimental evidence supporting this idea as significantly higher rates of acute animal death and rupture of veins occurred in the cerebral cortex and spinal cord of GFAP KO mice after concussive brain injury[1,2] . While the authors proposed that astrocytes lacking GFAP are impaired in their ability to protect the CNS, lack of GFAP in astrocyte endfeet was not causally linked to structural damage of the vasculature and it remained unresolved if the latter induced animal death.

My thesis project tests the hypothesis that astrocytes promote vascular stability through expression of GFAP in their endfeet.

1. Brenner M. Role of GFAP in CNS injuries. Neurosci. Lett. 2014. 565, 7-13.

2. Nawashiro H., Messing A., Azzam N., and Brenner M. Mice lacking GFAP are hypersensitive to traumatic cerebrospinal injury. Neuroreport. 1998. 9(8), 1691-6