期刊
JOURNAL OF NEUROCHEMISTRY
卷 135, 期 2, 页码 301-308出版社
WILEY
DOI: 10.1111/jnc.13248
关键词
blood-brain barrier; glucagon-like peptide-1; hippocampal formation; tau hyperphosphorylation; type 2 diabetes
资金
- National Natural Science Foundation of China (NSFC) [81370941, 81400334]
- Huazhong University of Science and Technology [2014TS071]
- China International Medical Foundation (CIMF)-Novo Nordisk China Diabetes Young Scientific Talent Research Funding
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 (3-3.5weeks) were daily injected subcutaneously with liraglutide (n=27), insulin (n=27), or saline (n=26), and five to seven mice were killed every 2weeks 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 similar to 1mIU/L by the end of 8weeks 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.
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