Tau neurofibrillary pathology and microtubule stability.
We previously reported that nonomolar concentrations of Taxol and several structurally diverse microtubule (MT)-stabilizing agents significantly enhanced the survival of neurons in the presence of fibrils of amyloid beta peptide (Abeta). Pretreatment of neurons with MT-stabilizing drugs also blocked Abeta-induced activation of tau hyperphosphorylation. Although tau is a substrate for several kinases, we initially focused on cdk5, as this tau kinase has been shown to be activated in Abeta-treated neurons and Alzheimer's disease (AD) brain. In an in vitro kinase assay, Taxol inhibited activation of cdk5 by Abeta. In addition, the proposed cellular cascade in which calpain activation leads to cleavage of the cdk5 regulator, p35, to the strong kinase activator p25 was also prevented. Taxol did not directly inhibit the activity of either cdk5 or calpain, indicating that other cellular components are required for the effect of the drug on Abeta activation of tau phosphorylation. Our results suggest that drugs that interact with MTs can alter signaling events in neurons, possibly because some MTs play a role in organizing protein complexes involved in responses to Abeta. Thus the cytoskeletal network may serve as a biosensor of cellular well-being.
Michaelis
Mary L
ML
Department of Pharmacology and Toxicology, University of Kansas, Malott Hall 5064, 1251 Wescoe Hall Drive, Lawrence, KS 66045-7582, USA. mlm@ku.edu
Dobrowsky
Rick T
RT
Li
Guibin
G
D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016875:tau Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D018844:Cyclin-Dependent Kinases; D017239:Paclitaxel