The intermediate filament (IF) network is a key component of the cell's cytoskeleton that warrants cell integrity and resilience. Recently, important novel IF network functions have emerged: it transduces biomechanical and molecular signals and it controls many associated proteins. Astrocytes express the IF protein Glial Fibrillary Acidic protein (GFAP). Over the last years, we identified novel GFAP splice isoforms, which are expressed in different subtypes of astrocytes in the developing and the adult human brain [1, 2]. GFAPd is specifically expressed in radial glial cells and in subventricular zone (SVZ) neural progenitors in the developing human cortex and in SVZ astrocytes in the adult human brain. The out-of-frame splice variants that can be detected by the GFAP+1 antibody are mainly expressed in a small number of astrocytes containing very long processes. These specific isoforms are not expressed during brain development or in brains of young healthy adults. Interestingly, we have observed that the expression of GFAP+1 correlates positively with the number of amyloid plaques in brains of Alzheimer patients. The exact function of the specialized IF network in the neurogenic SVZ astrocytes and the astrocytes near amyloid plaques is still elusive. The research in my group is currently aimed at understanding the functional changes in these cells induced by the specific composition of the IF-network. We have set up astrocyte and neurosphere cultures isolated from post-mortem human brains to enable to study the different astrocyte subtypes and the function of the different GFAP isoforms. We ultimately aim to develop novel therapeutic approaches by targeting reactive astrocytes and the astrocytic neural stem cells.

[1] Hol, E.M., Roelofs, R.F., Moraal, E.M., Sonnemans, M.A.F., Sluijs, J.A., Proper, E.A., De Graan, P.N.E., Fischer, D.F., and Van Leeuwen, F.W. Mol. Psychiatry, 8 (2003) 786-796.

[2] Roelofs, R.F., Fischer, D.F., Houtman, S.H., Sluijs, J.A., van Haren, W., van Leeuwen, F.W. and Hol, E.M. Glia 52 (2005) 289-300.