There is growing evidence that cytoskeletal instability of neuronal cells is an important step towards tangle formation and subsequent functional disconnection in the AD brain.
Sabeluzole, a new
drug in clinical 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 cytoskeleton was investigated. Previous studies have shown that in human TR14
neuroblastoma cells and in rat hippocampal neurons a hyperstimulating medium of
kinase activators leads to induction of aberrant tau phosphorylation followed by neurotoxicity. This report documents the attenuation of this neurotoxicity by
sabeluzole. By selective permeabilization procedures and quantitative immunocytochemistry we show that the compound is found to preferentially increase the fraction of polymerized
tubulin. Evidence is presented that the compound differentially modulates a
nocodazole-induced depolymerization in contrast to a cold-induced depolymerization. In the mouse, N4
neuroblastoma cells
sabeluzole decreases the spontaneous retraction frequency of neurites and lowers the lateral mobility of the cells. We, therefore, propose that
sabeluzole exerts its
neuroprotective effect by a stabilization of the neuronal cytoskeleton and that this mechanism provides a completely new approach for treatment in
Alzheimer's disease.