Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway.
Several lines of biochemical evidence correlate the presence of energy metabolic defects with the functional alterations associated with brain aging and 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 cells. Our findings show that insulin promotes APP metabolism by a glucose-independent mechanism. We demonstrate a novel intracellular pathway that increases the rate of secretion of soluble APP through the activity of phosphatidyl-inositol 3 kinase (PI3-K). This pathway, downstream of insulin receptor tyrosine kinase activity, does not involve either the activation of protein kinase C or the mitogen-activated protein kinase (MAP-K) pathway. Because of the physiological role of PI3-K in the translocation of glucose transporter-containing vesicles, we speculate that PI3-K involvement in APP metabolism may act at the level of vesicular trafficking.
Solano
D C
DC
Institute of Pharmacological Sciences, University of Milano, Milan, Italy.
Sironi
M
M
Bonfini
C
C
Solerte
S B
SB
Govoni
S
S
Racchi
M
M
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D005947:Glucose