| First Author | Ma DL | Year | 2015 |
| Journal | J Neurochem | Volume | 135 |
| Issue | 2 | Pages | 301-8 |
| PubMed ID | 26183127 | Mgi Jnum | J:226075 |
| Mgi Id | MGI:5695730 | Doi | 10.1111/jnc.13248 |
| Citation | Ma DL, et al. (2015) Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice. J Neurochem 135(2):301-8 |
| abstractText | Increasing evidence has shown that type 2 diabetes (T2D) is a risk factor for Alzheimer's disease. Neurofibrillary tangles, which consist of hyperphosphorylated tau and misfolded microtubules, is one of the neuropathological hallmarks of Alzheimer's disease. Db/db mice, a rodent model of T2D, also exhibited age-dependent tau hyperphosphorylation. Glucagon-like peptide-1 (GLP-1) mimetics, a type of drug used in T2D, has been found to have neuroprotective effects. The aim of this study was to explore the potential effects of liraglutide (a GLP-1 analog), or insulin, on tau phosphorylation in T2D animals. Male db/db mice (3-3.5 weeks) were daily injected subcutaneously with liraglutide (n = 27), insulin (n = 27), or saline (n = 26), and five to seven mice were killed every 2 weeks for analysis of plasma and cerebrospinal (CSF) insulin levels by ELISA, and protein levels in the hippocampal formation by western blot. We found that db/db mice treated with saline exhibited an age-dependent decrease in CSF insulin and an increase in hippocampal tau phosphorylation. Liraglutide injection reversed the CSF insulin to ~1 mIU/L by the end of 8 weeks treatment, and prevented the hyperphosphorylation of tau protein in the hippocampal formation. By contrast, insulin injection had no effects on CSF insulin or phosphorylation of tau protein. In summary, this study indicates that early GLP-1 analog intervention prevented the age-dependent tau hyperphosphorylation in T2D mice brain, probably by facilitating sequential activation in an insulin signaling pathway reflected in increased basal activation of Akt and basal suppression of glycogen synthase kinase-3 beta. We found that liraglutide, a GLP-1 (glucagon-like peptide-1) analog, prevented the age-dependent Alzheimer-like tau hyperphosphorylation in diabetic db/db mice. We proposed that liraglutide crosses the blood-brain barrier, and binds GLP-1 receptors from which G beta gamma dissociates intracellularly to activate PI3K, resulting in activation of Akt, which suppress GSK-3beta (glycogen synthase kinase-3beta), and thereby prevents it from phosphorylating tau. IRS-1: insulin receptor substrate 1; IRS-2: insulin receptor substrate 2; PI3K: phosphatidylinositol 3-kinase. |
