Insulin-like growth factor-1 and insulin mediate transient site-selective increases in tau phosphorylation in primary cortical neurons.
The modulation of tau phosphorylation and localization in response to insulin-like growth factor-1 or insulin was examined in primary cultures of rat cortical neurons. Insulin and insulin-like growth factor-1 treatment resulted in a rapid and transient increase in tau phosphorylation at specific epitopes. These effects were completely inhibited by lithium, revealing that the insulin and insulin-like growth factor-1 induced changes in tau phosphorylation were mediated by glycogen synthase kinase-3beta. In addition, the increase in tau phosphorylation directly correlated with a transient dissociation of tau from the cytoskeleton, indicating that insulin and insulin-like growth factor-1 treatment resulted in a change in tau localization. Using immunocytochemistry, it was also demonstrated that treatment of neurons with insulin-like growth factor-1 for 3 min resulted in a redistribution of tau to the growth cone and the distal segment of the axons. Further, insulin-like growth factor-1 treatment resulted in an increased immunoreactivity with the phospho-dependent antibody AT8 in the same areas of the axons. Thus, the phosphorylation state and distribution of tau can be modulated by insulin and insulin-like growth factor-1 signaling pathways involving glycogen synthase kinase-3beta. We propose that by transiently increasing tau phosphorylation, insulin and insulin-like growth factor-1 may contribute to the reorganization of the cytoskeleton necessary for the development and growth of the neurites.
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Alabama 35294, USA.
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D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D004622:Embryo, Mammalian; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
D007004:Hypoglycemic Agents; D007328:Insulin; D016875:tau Proteins; D007334:Insulin-Like Growth Factor I