Estudio del posible sinergismo en la neurodegeneración inducida por sobrexpresión de GKS-3B y por mutaciones de tau mediante coexpresión en modelos de ratón

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid. Facultad de Ciencias. Departamento de Biología Molecular. Fecha de lectura: 08-07-2005The neuropathological hallmarks of Alzheimer's disease include amyloid-P plaques and neurofibrillary tangles fonned by phosphorylated tau protein. GSK-3 is a proline-directed serinelthreonine kinase that has been postulated to have a role in Alzheimer's disease through its involvement in tau phosphorylation, B-arnyloid production, and mutated Preselinin-1 pathogenic effects. Tau modification induced by P-amyloid through GSK-3 activation has been shown to be a key to exert toxicity. On the other hand mutations in tau gene are enough to tngger a similar neurodegenerative disease (FTDP-17). To study if both types of tau modifications implicated in pathogenesis, i.e. phosphorylation and mutation can act synergistically we have combined TetIGSK-3P transgenic mice overexpressing the enzyme GSK-3P, with VLW transgenic mice expressing a mutant tau form present in FTDP-17, which develop prefibrillar tau-aggregates. Synergistic phosphorylation in PHF-1, AT-8, AT180 and 12E8 epitopes is obtained in the triple transgenic mice (TetIGSK-3PNLW) in CAI region, the hippocarnpal area were both transgenic proteins are overexpressed. In addition, more mature tau filaments could be purified from triple transgenic mice than from single transgenic mice. Neurodegeneration of hyppocampal dentate gyrus was also obsewed in the triple transgenic mice. We also tested the possibility of an impainnent of the ubiquitin-proteasome system, postulated to be one of the causes of Alzheimer's disease and related tauopathies. TetIGSK-3PNLW mice were crossed with a mouse expressing a fluorescent reporter protein, GFP, tagged for efficient degradation by the UPS (GFP-Ub mice). In theses mice we found accumulation of the reporter protein thus suggesting a dysfunction of the ubiquitin-proteasome system. Al1 these morphological, biochemical and functional data demonstrate that there is a synergistic contribution of both mutant tau and increased GSK-3 to induce neurodegeneration that is similar to that found in Alzheimer's disease and related tauopathies. Our data suggest that the use of GSK-3 inhibitors for AD therapeutics might also be extended to tauopathies caused by point mutations in tau gene