Attempt to develop animal model for the formation of paired helical filaments in the brains of Alzheimer's disease patients via sustained inactivation of integrin-linked kinase in mouse brain.

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Integrin-linked kinase (ILK) is a focal adhesion serin/threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK inactivation results in aberrant tau phosphorylation, which is identical to some of the aberrant phosphorylation sites in paired helical filaments in the brains of patients with Alzheimer's disease, via sustained activation of GSK-3β in cultured N1E-115 cells. In this study, we examined whether sustained inactivation of ILK leads to aberrant tau phosphorylation and produces paired helical filaments in mouse brain. Transfection and expression of a kinase-deficient mutant of ILK (DN-ILK), which behaves as a dominant negative, to mouse brain in vivo lead to inhibition of ILK activity and increase in active form of GSK-3β, and then induce aberrant tau phosphorylation in the hippocampus 3 wk after the transfection. However, the inhibition of endogenous ILK activity induced by DN-ILK is not retained and recovered to the basal level via a marked increase of endogenous ILK protein 12 wk after DN-ILK transfection. This compensatory mechanism leads the active form of GSK-3β to normal level and results in a decrease in the levels of aberrant tau phosphorylation. These results strongly suggest that ILK protects against aberrant tau phosphorylation via inhibition of GSK-3β activity in vivo. Although we could not create the mouse model for paired helical filaments in the brains of patients with Alzheimer's disease, our results imply that medical drugs to activate ILK activity might be effective in the therapy of patients with the early stage of Alzheimer's disease. Further studies are required to elucidate the compensatory mechanism after ILK inactivation in the brain.