Protection against beta-amyloid toxicity in primary neurons by paclitaxel (Taxol).
Neurofibrillary tangles in Alzheimer's disease contain aggregates of abnormally phosphorylated microtubule-associated protein tau, indicating that microtubule breakdown is a primary event in the neurodegenerative cascade. Recent studies have shown that addition to neuronal cultures of amyloid peptides found in Alzheimer's leads to abnormal phosphorylation of tau and neurofibrillary pathology. We tested the possibility that the microtubule-stabilizing drug paclitaxel (Taxol) might protect primary neurons against amyloid-induced toxicity. Neurons exposed to aggregated amyloid peptides 25-35 and 1-42 became pyknotic with degenerating neurites within 24 h. Treatment of cultures with paclitaxel either 2 h before or 2 h after addition of the peptide prevented these morphological alterations. When numbers of viable cells were determined in cultures exposed to amyloid peptide with or without paclitaxel for 24 or 96 h, the percentage of surviving cells was significantly higher in paclitaxel-treated cultures, and activation of the apoptosis-associated protease CPP32 was significantly reduced. These observations indicate that microtubule-stabilizing drugs may help slow development of the neurofibrillary pathology that leads to the loss of neuronal integrity in Alzheimer's disease.
Michaelis
M L
ML
Department of Pharmacology/Toxicology, University of Kansas, Lawrence 66045, USA.
Ranciat
N
N
Chen
Y
Y
Bechtel
M
M
Ragan
R
R
Hepperle
M
M
Liu
Y
Y
Georg
G
G
D016229:Amyloid beta-Peptides / Q000506:poisoning*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D009474:Neurons / Q000187:drug effects*; D017239:Paclitaxel / Q000494:pharmacology*; D010446:Peptide Fragments / Q000506:poisoning*; D051381:Rats / Q000196:embryology; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D017239:Paclitaxel