PROTECTION AGAINST BETA-AMYLOID TOXICITY IN PRIMARY NEURONS BY PACLITAXEL (TAXOL)

Neurofibrillary tangles in Alzheimer's disease contain aggregates of a bnormally phosphorylated microtubule-associated protein tau, indicatin g that microtubule breakdown is a primary event in the neurodegenerati ve cascade, Recent studies have shown that addition to neuronal cultur es of amyloid peptides found in Alzheimer's leads to abnormal phosphor ylation of tau and neurofibrillary pathology. We tested the possibilit y that the microtubule-stabilizing drug paclitaxel (Taxol) might prote ct primary neurons against amyloid-induced toxicity. Neurons exposed t o aggregated amyloid peptides 25-35 and 1-42 became pyknotic with dege nerating neurites within 24 h, Treatment of cultures with paclitaxel e ither 2 h before or 2 h after addition of the peptide prevented these morphological alterations. When numbers of viable cells were determine d in cultures exposed to amyloid peptide with or without paclitaxel fo r 24 or 96 h, the percentage of surviving cells was significantly high er in paclitaxel-treated cultures, and activation of the apoptosis-ass ociated protease CPP32 was significantly reduced. These observations i ndicate that microtubule-stabilizing drugs may help slow development o f the neurofibrillary pathology that leads to the loss of neuronal int egrity in Alzheimer's disease.