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
Article first published online: 14 JUL 2008
Copyright © 2008 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 86, Issue 15, pages 3265–3274, 15 November 2008
How to Cite
Jolivalt, C.G., Lee, C.A., Beiswenger, K.K., Smith, J.L., Orlov, M., Torrance, M.A. and Masliah, E. (2008), 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. J. Neurosci. Res., 86: 3265–3274. doi: 10.1002/jnr.21787
- Issue published online: 21 OCT 2008
- Article first published online: 14 JUL 2008
- Manuscript Accepted: 27 APR 2008
- Manuscript Revised: 14 APR 2008
- Manuscript Received: 27 FEB 2008
- Institute for the Study of Aging
- insulin pathway;
- amyloid β
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. © 2008 Wiley-Liss, Inc.