Defective insulin signaling pathway and increased glycogen synthase kinase‐3 activity in the brain of diabetic mice: Parallels with Alzheimer's disease and correction by insulin
- 14 July 2008
- journal article
- research article
- Published by Wiley in Journal of Neuroscience Research
- Vol. 86 (15), 3265-3274
- https://doi.org/10.1002/jnr.21787
Abstract
We have evaluated the effect of peripheral insulin deficiency on brain insulin pathway activity in a mouse model of type 1 diabetes, the parallels with Alzheimer's disease (AD), and the effect of treatment with insulin. Nine weeks of insulin‐deficient diabetes significantly impaired the learning capacity of mice, significantly reduced insulin‐degrading enzyme protein expression, and significantly reduced phosphorylation of the insulin‐receptor and AKT. Phosphorylation of glycogen synthase kinase‐3 (GSK3) was also significantly decreased, indicating increased GSK3 activity. This evidence of reduced insulin signaling was associated with a concomitant increase in tau phosphorylation and amyloid β protein levels. Changes in phosphorylation levels of insulin receptor, GSK3, and tau were not observed in the brain of db/db mice, a model of type 2 diabetes, after a similar duration (8 weeks) of diabetes. Treatment with insulin from onset of diabetes partially restored the phosphorylation of insulin receptor and of GSK3, partially reduced the level of phosphorylated tau in the brain, and partially improved learning ability in insulin‐deficient diabetic mice. Our data indicate that mice with systemic insulin deficiency display evidence of reduced insulin signaling pathway activity in the brain that is associated with biochemical and behavioral features of AD and that it can be corrected by insulin treatment.Keywords
This publication has 58 references indexed in Scilit:
- Insulin signaling effects on memory and moodCurrent Opinion in Pharmacology, 2007
- Regulation of phosphorylation of tau by cyclin‐dependent kinase 5 and glycogen synthase kinase‐3 at substrate levelFEBS Letters, 2006
- Diabetes and Alzheimer's Disease - Is There a Connection?The Review of Diabetic Studies, 2006
- The glamour and gloom of glycogen synthase kinase-3Trends in Biochemical Sciences, 2004
- The multifaceted roles of glycogen synthase kinase 3β in cellular signalingProgress in Neurobiology, 2001
- Brain insulin and insulin receptors in aging and sporadic Alzheimer's diseaseJournal of Neural Transmission, 1998
- Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase BNature, 1995
- Alzheimer's β‐amyloid peptide specifically interacts with and is degraded by insulin degrading enzymeFEBS Letters, 1994
- Effects of insulin-dependent diabetes on learning and memory efficiency in adultsJournal of Clinical and Experimental Neuropsychology, 1993
- Pathological changes in the central and peripheral nervous system of young long-term diabeticsDiabetologia, 1968