title: Exendin-4, a glucagon-like peptide-1 receptor agonist, reduces Alzheimer disease-associated tau hyperphosphorylation in the hippocampus of rats with type 2 diabetes.
abstract: BACKGROUND
  Impaired insulin signaling pathway in the brain in type 2 diabetes (T2D) is a risk factor for Alzheimer disease (AD). Glucagon-like peptide-1 (GLP-1) and its receptor agonist are widely used for treatment of T2D. Here we studied whether the effects of exendin-4 (EX-4), a long-lasting GLP-1 receptor agonist, could reduce the risk of AD in T2D.
  
  
  METHODS
  Type 2 diabetes rats were injected with EX-4 for 28 consecutive days. Blood glucose and insulin levels, as well as GLP-1 and insulin in cerebrospinal fluid, were determined during the experiment. The phosphorylation level of tau at individual phosphorylation sites, the activities of phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), and glycogen synthase kinase-3β (GSK-3β) were analyzed with Western blots.
  
  
  RESULTS
  The levels of phosphorylated tau protein at site Ser199/202 and Thr217 level in the hippocampus of T2D rats were found to be raised notably and evidently decreased after EX-4 intervention. In addition, brain insulin signaling pathway was ameliorated after EX-4 treatment, and this result was reflected by a decreased activity of PI3K/AKT and an increased activity of GSK-3β in the hippocampus of T2D rats as well as a rise in PI3K/AKT activity and a decline in GSK-3β activity after 4 weeks intervention of EX-4.
  
  
  CONCLUSIONS
  These results demonstrate that multiple days with EX-4 appears to prevent the hyperphosphorylation of AD-associated tau protein due to increased insulin signaling pathway in the brain. These findings support the potential use of GLP-1 for the prevention and treatment of AD in individuals with T2D.
authors.affiliation: From the Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Weijie
authors.initials: W
authors.lastname: Xu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhu
authors.forename: Delin
authors.initials: D
authors.lastname: Ma
authors.forename: Shuhong
authors.initials: S
authors.lastname: Hu
mesh_terms: D000544:Alzheimer Disease / Q000097:blood / Q000150:complications* / Q000188:drug therapy*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications* / Q000188:drug therapy; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006943:Hyperglycemia / Q000150:complications / Q000188:drug therapy; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D014688:Venoms / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D016875:tau Proteins; D000077270:Exenatide; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3