Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway

Several lines of biochemical evidence correlate the presence of energy meta bolic defects with the functional alterations associated with brain aging a nd with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context we tested the ability of insulin to regulate the amyloid precursor protein (APP) processing in SH-SY5Y neuroblastoma cel ls. Our findings show that insulin promotes APP metabolism by a glucose-ind ependent mechanism, We demonstrate ai novel intracellular pathway that incr eases the rate of secretion of soluble APP through the activity of phosphat idyl-inositol 3 kinase (PI3-K). This pathway, downstream of insulin recepto r tyrosine kinase activity, does not involve either the activation of prote in kinase C or the mitogen-activated protein kinase (MAP-K) pathway. Becaus e of the physiological role of PI3-K in the translocation of glucose transp orter-containing vesicles, we speculate that PI3-K involvement in APP metab olism may act at the level of vesicular trafficking.