title: Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice.
abstract: 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.
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: De-Lin
authors.initials: DL
authors.lastname: Ma
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fu-Qiong
authors.initials: FQ
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wei-Jie
authors.initials: WJ
authors.lastname: Xu
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Wen-Zhu
authors.initials: WZ
authors.lastname: Yue
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000378:metabolism*; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000134:cerebrospinal fluid / Q000494:pharmacology; D007333:Insulin Resistance; D000069450:Liraglutide / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D051058:Oncogene Protein v-akt / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D016875:tau Proteins; D000069450:Liraglutide; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3
keywords: blood-brain barrier; glucagon-like peptide-1; hippocampal formation; tau hyperphosphorylation; type 2 diabetes