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.
Lesort
M
M
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Alabama 35294, USA.
Johnson
G V
GV
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