β-Amyloid-induced neurodegeneration and protection by structurally diverse microtubule-stabilizing agents

M. L. Michaelis, S. Ansar, Y. Chen, E. R. Reiff, K. I. Seyb, R. H. Himes, K. L. Audus, G. I. Georg

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78 Scopus citations

Abstract

Deposition of β-amyloid peptide (Aβ) and hyperphosphorylation of the τ protein are associated with neuronal dysfunction and cell death in Alzheimer's disease. Although the relationship between these two processes is not yet understood, studies have shown that both in vitro and in vivo exposure of neurons to Aβ leads to τ hyperphosphorylation and neuronal dystrophy. We previously reported that the microtubule-stabilizing drug paclitaxel (Taxol) protects primary neurons against toxicity induced by the Aβ25-35 peptide. The studies in this report were undertaken to characterize the actions of paclitaxel more fully, to assess the effectiveness of structurally diverse microtubule-stabilizing agents in protecting neurons, and to determine the time course of the protective effects of the drugs. Primary neurons were exposed to Aβ in the presence or absence of several agents shown to interact with microtubules, and neuronal survival was monitored. Paclitaxel protected neurons against Aβ1-42 toxicity, and paclitaxel-treated cultures exposed to Aβ showed enhanced survival over Aβ-only cultures for several days. Neuronal apoptosis induced by Aβ was blocked by paclitaxel. Other taxanes and three structurally diverse microtubule-stabilizing compounds also significantly increased survival of Aβ-treated cultures. At concentrations below 100 nM, the drugs that protected the neurons did not produce detectable toxicity when added to the cultures alone. Although multiple mechanisms are likely to contribute to the neuronal cell death induced by oligomeric or fibrillar forms of Aβ, low concentrations of drugs that preserve the integrity of the cytoskeletal network may help neurons survive the toxic cascades initiated by these peptides.

Original languageEnglish (US)
Pages (from-to)659-668
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume312
Issue number2
DOIs
StatePublished - Feb 2005

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