Stabilization of the cyclin‐dependent kinase 5 activator, p35, by paclitaxel decreases β‐amyloid toxicity in cortical neurons

Abstract

One hallmark of Alzheimer's disease (AD) is the formation of neurofibrillary tangles, aggregated paired helical filaments composed of hyperphosphorylated tau. Amyloid-b (Ab) induces tau hyperphosphorylation, decreases microtubule (MT) stability and induces neuronal death. MT stabilizing agents have been proposed as potential therapeutics that may minimize Ab toxicity and here we report that paclitaxel (taxol) prevents cell death induced by Ab peptides, inhibits Abinduced activation of cyclin-dependent kinase 5 (cdk5) and decreases tau hyperphosphorylation. Taxol did not inhibit cdk5 directly but significantly blocked Ab-induced calpain activation and decreased formation of the cdk5 activator, p25, from p35. Taxol specifically inhibited the Ab-induced activation of the cytosolic cdk5-p25 complex, but not the membraneassociated cdk5-p35 complex. MT-stabilization was necessary for neuroprotection and inhibition of cdk5 but was not sufficient to prevent cell death induced by overexpression of p25. As taxol is not permeable to the blood-brain barrier, we assessed the potential of taxanes to attenuate Ab toxicity in adult animals using a succinylated taxol analog (TX67) permeable to the blood-brain barrier. TX67, but not taxol, attenuated the magnitude of both basal and Ab-induced cdk5 activation in acutely dissociated cortical cultures prepared from drug treated adult mice. These results suggest that MT-stabilizing agents may provide a therapeutic approach to decrease Ab toxicity and neurofibrillary pathology in AD and other tauopathies.

Effects of Cell Cycle Inhibitors on Tau Phosphorylation in N2aTau3R Cells

“…Treatment with paclitaxel restores fast axonal transport in spinal axons, increases axonal MTs, and ameliorates motor impairments in tau transgenic mice that developed filamentous tau inclusions (mostly in the spinal cord) (Ishihara et al 1999(Ishihara et al , 2001Zhang et al 2005). Paclitaxel also blocks Aβ-induced phosphorylation of tau by preventing the cleavage of p35 by calpain (Li et al 2003). Nanomolar concentrations of paclitaxel can protect neurons against various toxic insults and enhance survival by maintaining Ca 2+ homeostasis (Burke et al 1994;Furukawa and Mattson 1995;Furukawa et al 2003;Sponne et al 2003;Michaelis et al 2005) without evidence of toxicity (Trushina et al 2003).…”

β-Amyloid-Induced Neurodegeneration and Protection by Structurally Diverse Microtubule-Stabilizing Agents

“…Highly phosphorylated no longer stabilizes MTs, and intracellular aggregates of the protein are believed to cause disturbances in axonal transport of molecules and organelles in affected neurons (Lee, 1995). Recent studies have suggested that deposition of A␤ enhances phosphorylation in vitro in neuronal cell cultures (Busciglio et al, 1995;Ferreira et al, 1997;Grace et al, 2002;Li et al, 2003) and in vivo when A␤ is deposited in the brain (Sigurdsson et al, 1997;Geula et al, 1998).…”

“…We previously reported that the MT-stabilizing agent paclitaxel (Taxol) significantly enhanced the survival of primary neurons in culture following exposure to A␤ [25][26][27][28][29][30][31][32][33][34][35] peptides, reduced activation of the apoptotic protease caspase 3, and blocked A␤-induced increases in abnormal phosphorylation (Michaelis et al, 1998;Li et al, 2003).…”

A functional genomic study on NCI's anticancer drug screen

“…It is reported that taxol prevents cell death induced by Abeta peptides, inhibits Abeta-induced activation of cdk5 and decreases tau hyperphosphorylation. 32 Taxol does not inhibit cdk5 directly but significantly blocks Abeta-induced calpain activation.…”