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. 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.

Insulin resistance and Parkinson’s disease: A new target for disease modification?

“…In view of the fact that increased levels of phosphorylated IRS-1 has been identified as the primary cause of neuronal insulin resistance in AD, (and have also been implicated in PD) exenatide and liraglutide have also demonstrated the ability to reduce levels of IRS-1 pS616 and IRS-1 pS36 in the APP/PS1 model of AD and diabetic mice. This has been shown to not only lead to facilitation of insulin signalling, but the restoration of normal tissue responses to insulin (Bomfim et al, 2012;Long-Smith et al, 2013;Ma et al, 2015), resulting in improvements in AD pathology and functional improvements in cognition. These beneficial effects on neuronal insulin resistance and restoration of insulin signalling essentially restores and increases the basal activation of the AKT pathway, activating signalling cascades that ultimately promote cellular survival.…”

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

“…Liraglutide, a glucagon-like peptide 1 (GLP-1) analog that stimulates insulin secretion, prevents aberrant tau phosphorylation in a mouse model of type II diabetes [55] and significantly reduces aberrantly phosphorylated tau and improves motor function in a mouse model of tauopathy (hTauP301L) [56]. Similarly, linagliptin has also recently been reported to reduce aberrant tau phosphorylation and improve cognition in 3xTg-AD mice [57].…”

Dynamics of diabetes and obesity: Epidemiological perspective

“…The mechanistic link between AD and diabetes is still unknown and recent literature suggesting inflammatory response, IR insulin growth factor (IGF) signaling, ApoEε4 allele on synaptic plasticity, acetylcholine esterase activity and vascular dysregulation of brain capillaries would play crucial role in forming pathophysiologic changes relating diabetes to dementia, including white matter disease, breakdown of the blood brain barrier, inflammation, and others [49–58]. Type 3 diabetes also effects glycogen synthase kinase 3β (GSK3β) signaling on Tau phosphorylation, and thus effect on mitochondria in terms to decrease or loss of ATP production [51–54] (Figure 2). …”