Insulin-induced neurite-like process outgrowth: Acceleration of tau protein synthesis via a phosphoinositide 3-kinase∼mammalian target of rapamycin pathway

Both insulin and tau, promoting neuronal differentiation (neurite outgrowth, neuronal polarity, and myelination) and cell survival, are associated with neurodegenerative disease (e.g., Alzheimer’s disease). The aim of this study was to explore relation between insulin-induced activation of insulin signal and expression of tau protein on neurite-like process outgrowth in adrenal chromaffin cells. Primary cultured bovine adrenal chromaffin cells were incubated with insulin to determine whether stimulant of insulin signal could affect tau expression and neurite-like process outgrowth. Chronic treatment with insulin (⩾6 h) led neurite-like process outgrowth as well as increased tau protein level by ∼99% in a concentration (EC50 5.5 nM)- and time-dependent manner, without changing Ser396-phosphorylated tau level. The insulin-induced increase of tau protein level was abolished by LY294002 [an inhibitor of phosphoinositide 3-kinase (PI3K)] and rapamycin [an inhibitor of mammalian target of rapamycin (mTOR)], but not by PD98059 and U0126 [two inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK)]. Additionally, insulin-induced increase of tau was blocked by cyclohexamide (an inhibitor of protein synthesis), but not by actinomycin D (an inhibitor of gene transcription). Pulse-label followed by polyacrylamide gel electrophoresis revealed that insulin accelerated tau protein synthesis rate (t1/2) from 2.6 to 1.9 h. Insulin did not change tau mRNA level. Taken together, these results suggest that insulin-induced activation of PI3K∼mTOR pathway up-regulated tau protein via acceleration of protein synthesis, on which insulin promoted neurite-like process outgrowth.

► Little is known of a definite relationship between insulin and tau expression.
► Both of them promote neuronal cell function.
► Insulin up-regulates tau expression via protein synthesis.
► Insulin treatment will be possible to contribute neuronal cell differentiation.