Stabilization of the cyclin-dependent kinase 5 activator, p35, by paclitaxel decreases beta-amyloid toxicity in cortical neurons.
One hallmark of Alzheimer's disease (AD) is the formation of neurofibrillary tangles, aggregated paired helical filaments composed of hyperphosphorylated tau. Amyloid-beta (Abeta) induces tau hyperphosphorylation, decreases microtubule (MT) stability and induces neuronal death. MT stabilizing agents have been proposed as potential therapeutics that may minimize Abeta toxicity and here we report that paclitaxel (taxol) prevents cell death induced by Abeta peptides, inhibits Abeta-induced activation of cyclin-dependent kinase 5 (cdk5) and decreases tau hyperphosphorylation. Taxol did not inhibit cdk5 directly but significantly blocked Abeta-induced calpain activation and decreased formation of the cdk5 activator, p25, from p35. Taxol specifically inhibited the Abeta-induced activation of the cytosolic cdk5-p25 complex, but not the membrane-associated 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 Abeta 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 Abeta-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 Abeta toxicity and neurofibrillary pathology in AD and other tauopathies.
Li
Guibin
G
Department of Pharmacology and Toxicology, University of Kansas, Lawrence 66045, USA.
Faibushevich
Alexander
A
Turunen
Brandon J
BJ
Yoon
Sung Ok
SO
Georg
Gunda
G
Michaelis
Mary L
ML
Dobrowsky
Rick T
RT
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D046911:Macromolecular Substances; D051379:Mice; D008822:Mice, Transgenic; D008870:Microtubules / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D017239:Paclitaxel / Q000031:analogs & derivatives / Q000494:pharmacology*; D010446:Peptide Fragments / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D000972:Antineoplastic Agents, Phytogenic; D046911:Macromolecular Substances; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D021122:Protein Subunits; C074636:amyloid beta-protein (25-35); C089495:neuronal Cdk5 activator (p25-p35); D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel