SABELUZOLE STABILIZES THE NEURONAL CYTOSKELETON

There is growing evidence that cytoskeletal instability of neuronal ce lls is an important step towards tangle formation and subsequent funct ional disconnection in the AD brain. Sabeluzole, a new drug in clinica l trials for Alzheimer's disease (AD), has been shown to slow down the clinical progression of the disease. In a search for the mechanism of action of this compound, the effect of sabeluzole on the neuronal cyt oskeleton was investigated. Previous studies have shown that in human TR14 neuroblastoma cells and in rat hippocampal neurons a hyperstimula ting medium of kinase activators leads to induction of aberrant tau ph osphorylation followed by neurotoxicity. This report documents the att enuation of this neurotoxicity by sabeluzole. By selective permeabiliz ation procedures and quantitative immunocytochemistry we show that the compound is found to preferentially increase the fraction of polymeri zed tubulin. Evidence is presented that the compound differentially mo dulates a nocodazole-induced depolymerization in contrast to a cold-in duced depolymerization. In the mouse, N4 neuroblastoma cells sabeluzol e decreases the spontaneous retraction frequency of neurites and lower s the lateral mobility of the cells. We, therefore, propose that sabel uzole exerts its neuroprotective effect by a stabilization of the neur onal cytoskeleton and that this mechanism provides a completely new ap proach for treatment in Alzheimer's disease.