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. Keywords: blood-brain barrier, glucagon-like peptide-1, hippocampal formation, tau hyperphosphorylation, type 2 diabetes. J. Neurochem. (2015) 135, 301-308.Type 2 diabetes (T2D) is a risk factor for Alzheimer's disease (AD) (Tolppanen et al. 2013). One of the characteristic neuropathological changes in AD is the deposition of intracellular neurofibrillary tangles (NFTs), which consist of paired helical and straight filaments of abnormally hyperphosphorylated tau protein . The degree of dementia symptoms correlates strongly with neuronal and synaptic loss and the number of NFTs in AD brains (Arriagada et al. 1992), suggesting a crucial role of tau pathology in the disease. Aberrant hyperphosphorylation of tau is therefore considered critical to the progression of neurodegeneration in AD .T2D is characterized by peripheral insulin resistance that leads to glucose intolerance and hyperglycemia. There is evidence suggesting that defective insulin signaling may also occur in brains of T2D animals (Yamamoto et al. Abbreviations used: AD, Alzheimer's disease; BBB, blood-brain barrier; CSF, cerebrospinal fluid; GLP-1, glucagon-like peptide-1; GSK3a, glycogen synthase kinase-3a; GSK-3b, glycogen synthase kinase-3 beta; NFTs, neurofibrillary tangles; PI3K, phosphatidylinositol 3-kinase; T2D, type 2 diabetes mellitus.
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