Sabeluzole stabilizes the neuronal cytoskeleton

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 progr...

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Bibliographic Details
Published in:Neurobiology of aging 1996-07, Vol.17 (4), p.573-581
Main Authors: Geerts, Hugo, Nuydens, Rony, de Jong, Mirjam, Cornelissen, Frans, Nuyens, Roger, Wouters, Luc
Format: Article
Language:English
Subjects:
Alzheimer's disease
Animals
Biological and medical sciences
Cells, Cultured - drug effects
Cytoskeletal stability
Cytoskeleton - drug effects
Dose-Response Relationship, Drug
Humans
Medical sciences
Mice
Mice, Inbred Strains
Neuroblastoma - drug therapy
Neurons - drug effects
Neuropharmacology
Neuroprotective agent
Neurotoxicity
Pharmacology. Drug treatments
Piperidines - pharmacology
Rats
Sabeluzole
Tau phosphorylation
Thiazoles - pharmacology
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Summary: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.
ISSN:0197-4580
1558-1497
DOI:10.1016/0197-4580(96)00067-X