Sitagliptin increases tau phosphorylation in the hippocampus of rats with type 2 diabetes and in primary neuron cultures
Highlights
► Sitagliptin, dipeptidyl peptidase (DPP)-IV inhibitor, increases tau phosphorylation in type-2 diabetes model. ► Sitagliptin increases tau phosphorylation in primary neuronal cells. ► Sitagliptin's effect on tau phosphorylation is related with GSK3β activity.
Introduction
Alzheimer's disease (AD) is characterized by the progressive loss of neurons and synapses, and exhibits two principle pathologic characteristics: neurofibrillary tangles (NFT) and senile plaques (Gomez-Isla et al., 1997). NFTs are formed by intraneuronal accumulation of paired helical filaments composed of abnormally hyperphosphorylated tau protein (Grundke-Iqbal et al., 1986). Senile plaques contain β-amyloid peptide (Aβ), which arises through proteolytic processing of amyloid precursor protein (APP) by β-secretase (BACE-1) and γ-secretase (presenilin-1/2). Although the precise significance of these pathologic findings remains unclear, several studies have reported that the number of NFTs is strongly correlated with the degree of dementia in AD (Arriagada et al., 1992, Gomez-Isla et al., 1997, Mackay et al., 1997). Aberrant phosphorylation of tau is therefore considered a critical step in the progression of neurodegeneration in AD.
Cognitive dysfunction, including impaired memory performance, is evident in diabetes patients (Kodl and Seaquist, 2008, Perlmuter et al., 1984), and many clinical studies have shown that diabetes increases the risk of AD by two- to three-fold (Zhao and Townsend, 2009). Moreover, about 80% of AD patients have diabetes or abnormal blood glucose levels (Janson et al., 2004), and defects in insulin signaling are associated with the accumulation of NFTs and senile plaques in AD (Cole and Frautschy, 2006, Moloney et al., 2010). Many experimental diabetes animal models also show cognitive dysfunction and AD pathologies, including tau phosphorylation (Clodfelder-Miller et al., 2006, Li et al., 2007, Planel et al., 2007, Stranahan et al., 2008). Moreover, anti-diabetes drugs such as rosiglitazone, metformin, and glucagon-like peptide (GLP)-1 receptor agonists have been suggested to be effective in reducing AD-associated pathologies. There is considerable experimental evidence that rosiglitazone is effective in ameliorating Aβ and tau pathologies in AD and diabetes models in association with improved learning and memory (De Felice et al., 2009, Landreth et al., 2008, Yoon et al., 2010). The anti-diabetic agent metformin, a dimethylbiguanide, reduces tau phosphorylation in neurons of tau transgenic mice (Kickstein et al., 2010), and a GLP-1 receptor agonist reduces Aβ aggregation and cytotoxicity in AD models (Li et al., 2010). Thus, circumstances in which diabetes is associated with AD coupled with the fact that anti-diabetes drugs are effective in reducing AD pathology may further attract researchers to identify additional anti-diabetes drugs as new candidates for AD therapy.
Sitagliptin, an interesting anti-diabetes drug that has recently come on the market, acts through inhibition of dipeptidyl peptidase (DPP)-IV to increase GLP-1 levels and reduce blood glucose. Sitagliptin was recently reported to ameliorate Aβ deposition in AD models (D'Amico et al., 2010). However, no studies have addressed the effects of sitagliptin on tau pathology. Thus, we here administered the drug to Otsuka Long Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes (Yoon et al., 2010). Unexpectedly, we found for the first time that sitagliptin aggravated tau phosphorylation in the OLETF rat hippocampus, suggesting that caution be urged in considering the use of this drug in patients.
Section snippets
Animals
Male control Long Evans Tokushima Otsuka (LETO) and diabetic Otsuka Long Evans Tokushima Fatty (OLETF) rats were obtained from the Otsuka Pharmaceutical Company (Tokushima, Japan). Animals were maintained at a constant ambient temperature (22 °C ± 1 °C) with a 12 h:12 h light–dark cycle and free access to water and food. All procedures were approved by the Institutional Animal Care and Use Committee of the Asan Institute for Life Sciences in Seoul, Korea.
Administration of sitagliptin
OLETF rats (21 weeks old) were divided randomly
Aggravation of tau phosphorylation in the hippocampus of sitagliptin-treated OLETF rats
Tau phosphorylation increased in OLETF rats compared to control LETO rats (Fig. 1A). Western blot analyses showed that the levels of ser-199/202- and ser-396-phosphorylated tau were increased, and the level of dephosphorylated tau detected by an anti-Tau-1 antibody was decreased in sitagliptin-treated OLETF rats compared with control animals (Fig. 1B). This clearly shows that sitagliptin aggravated tau phosphorylation in the type 2 diabetes hippocampus.
Increased phosphorylation of GSK3β and Akt in sitagliptin-treated OLETF rats
To investigate how sitagliptin increased
Discussion
We found that sitagliptin aggravated brain tau phosphorylation in type 2 diabetes model rats and primary neurons. This result suggests to us that greater caution be urged in the use of sitagliptin for AD and other clinical applications, and indicate that there might be a relationship between physiological and pathological DPP-IV inhibition and the pathogenesis of AD.
We investigated activity-related post-translational changes in various tau kinases and phosphatases in an effort to identify an
Acknowledgments
We thank Professor Ki-Up Lee and Woo-Je Lee (Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine) for helpful discussions and generously supplying rats. This work was supported by grants from the National Research Foundation of Korea funded by the Korean government (2010-0029490) and the Korea Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A100047) and Basic Science Research Program through the National Research
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