Effect of taxoid and nontaxoid site microtubule-stabilizing agents on axonal transport of mitochondria in untransfected and ECFP-htau40-transfected rat cortical neurons in culture

摘要

An important aspect of synaptic plasticity in the brain is axonal transport of essential components such as mitochondria from the soma to the synapse. For uninterrupted transport of cellular cargo down the axon, functional microtubules are required. Altered microtubule dynamics induced by changes in expression of microtubule-associated tau protein affects normal microtubule function and interferes with axonal transport. Here we investigate the effects of the nontaxoid-binding-site microtubule-stabilizing agents peloruside A (PelA) and laulimalide, compared with the taxoid-site-binding agents paclitaxel (Ptx) and ixabepilone, on axonal transport of mitochondria in 1-day-old rat pup cerebral cortical neuron cultures. The differences in effects of these two types of compound on mitochondrial trafficking were specifically compared under conditions of excess tau expression. PelA and laulimalide had no adverse effects on their own on mitochondrial transport compared with Ptx and ixabepilone, which inhibited mitochondrial run length at higher concentrations. PelA, like Ptx, was able to partially reverse the blocked mitochondrial transport seen in ECFP-htau40-overexpressing neurons, although at higher concentrations of microtubule-stabilizing agent, the PelA response was improved over the Ptx response. These results support a neuroprotective effect of microtubule stabilization in maintaining axonal transport in neurons overexpressing tau protein and may be beneficial in reducing the severity of neurodegenerative diseases such as Alzheimer's disease.