title: {beta}-Amyloid-induced neurodegeneration and protection by structurally diverse microtubule-stabilizing agents.
abstract: Deposition of beta-amyloid peptide (Abeta) and hyperphosphorylation of the tau 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 Abeta leads to tau hyperphosphorylation and neuronal dystrophy. We previously reported that the microtubule-stabilizing drug paclitaxel (Taxol) protects primary neurons against toxicity induced by the Abeta(25-35) peptide. The studies in this report were undertaken to characterize the actions of paclitaxel more fully, to assess the effectiveness of structurally diverse microtubulestabilizing agents in protecting neurons, and to determine the time course of the protective effects of the drugs. Primary neurons were exposed to Abeta in the presence or absence of several agents shown to interact with microtubules, and neuronal survival was monitored. Paclitaxel protected neurons against Abeta(1-42) toxicity, and paclitaxel-treated cultures exposed to Abeta showed enhanced survival over Abeta-only cultures for several days. Neuronal apoptosis induced by Abeta was blocked by paclitaxel. Other taxanes and three structurally diverse microtubule-stabilizing compounds also significantly increased survival of Abeta-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 Abeta, low concentrations of drugs that preserve the integrity of the cytoskeletal network may help neurons survive the toxic cascades initiated by these peptides.
authors.affiliation: Department of Pharmacology and Toxicology, 1251 Wescoe Hall Dr., 5064 Malott Hall, University of Kansas, Lawrence, KS 66045, USA. mlm@ku.edu
authors.forename: M L
authors.initials: ML
authors.lastname: Michaelis
authors.forename: S
authors.initials: S
authors.lastname: Ansar
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: E R
authors.initials: ER
authors.lastname: Reiff
authors.forename: K I
authors.initials: KI
authors.lastname: Seyb
authors.forename: R H
authors.initials: RH
authors.lastname: Himes
authors.forename: K L
authors.initials: KL
authors.lastname: Audus
authors.forename: G I
authors.initials: GI
authors.lastname: Georg
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007700:Kinetics; D008870:Microtubules / Q000187:drug effects* / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000139:chemically induced* / Q000517:prevention & control*; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D000972:Antineoplastic Agents, Phytogenic; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C074636:amyloid beta-protein (25-35); D048031:JNK Mitogen-Activated Protein Kinases; D017239:Paclitaxel