Insulin inhibits Abeta fibrillogenesis through a decrease of the GM1 ganglioside-rich microdomain in neuronal membranes.
Type 2 diabetes is a risk factor for late-onset Alzheimer's disease. However, the underlying mechanisms remain unknown. To investigate whether insulin is associated with the assembly of amyloid beta-protein from the cell surface, we treated nerve growth factor (NGF)-treated rat pheochromocytoma 12 (PC12) cells with insulin, which is related to the development of diabetes. Insulin treatment induced a decrease in GM1 ganglioside (GM1) levels in detergent-resistant membrane microdomains of NGF-treated PC12 cells. The insulin-induced effects on GM1 levels were regulated by a phosphatidylinositol 3-kinase inhibitor, but not by an extracellular signal-regulated kinase inhibitor. Pre-treatment with a protein synthesis inhibitor did not inhibit the decrease in GM1 levels induced by insulin. In addition, insulin failed to induce formation of fibrils from soluble amyloid beta-protein or to accelerate GM1-induced fibril formation. Furthermore, assembly of amyloid beta-protein in cultures of NGF-treated PC12 cells was significantly decreased by insulin. These results suggest that insulin inhibits amyloid beta-protein assembly by decreasing GM1 expression in detergent-resistant membrane microdomains of neuronal membranes.
Laboratory of Neurochemistry, Department of Pharmacy, College of Pharmaceutical Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan.
Naoki
N
Yamamoto
Hideo
H
Taniura
Kenji
K
Suzuki
D000199:Actins / Q000096:biosynthesis; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D015153:Blotting, Western; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002738:Chloroquine / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D005456:Fluorescent Dyes; D005677:G(M1) Ganglioside / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008081:Liposomes; D009025:Morpholines / Q000494:pharmacology; D016874:Neurofibrillary Tangles / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats
D000199:Actins; D016229:Amyloid beta-Peptides; D005456:Fluorescent Dyes; D007004:Hypoglycemic Agents; D007328:Insulin; D008081:Liposomes; D009025:Morpholines; D011500:Protein Synthesis Inhibitors; D005677:G(M1) Ganglioside; C033110:RV 538; D002738:Chloroquine; D003513:Cycloheximide; D019869:Phosphatidylinositol 3-Kinases