Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice☆
Highlights
► The db/db mice have Alzheimer's disease-like brain changes. ► The increased phospho-tau at 396 may be due to JNK activation in the db/db mouse brain. ► Metformin attenuates the Alzheimer's disease-like brain biochemical changes in the db/db mice.
Introduction
Diabetes mellitus (DM) affects more than 20 million Americans (Cherian et al., 2009, Kim et al., 2009). Studies have shown that DM increases the risk for Alzheimer's disease (AD) (Brands et al., 2005, Ott et al., 1999, Strachan et al., 1997), the most common form of dementia in the elderly (Berg and Morris, 1994). The pathological hallmarks in the brain of a patient with AD are extracellular amyloid plaques formed by β-amyloid peptide (Aβ), an enzymatic product of amyloid precursor protein (APP) by β-secretase/β-amyloid converting enzyme 1 (BACE1) and γ-secretase (Vassar, 2004, Vassar and Citron, 2000), and intracellular neurofibrillary tangles consisting of hyperphosphorylated tau proteins (Selkoe, 2001). It has been suggested that Aβ and hyperphosphorylated tau proteins induce local neurotoxicity that ultimately results in AD.
There are at least two types of DM: type 1 and type 2. More patients suffer from type 2 DM (Cherian et al., 2009). Multiple animal models have been developed to facilitate DM research. It has been shown that animals with type 1 and type 2 DM have an increased phospho-tau expression in their brains (Jolivalt et al., 2008, Kim et al., 2009, Li et al., 2007, Planel et al., 2007b). These animals also have increased Aβ expression in the brains (Jolivalt et al., 2008, Li et al., 2007). Among animal models for DM, the db/db (BKS.Cg-Dock7m +/+ Leprdb/J) mice are a common model for type 2 DM. These mice develop hyperglycemia and hyperinsulinemia and are obese, polyphagic, polydipsic and polyuric (Fujita et al., 2002, Kim et al., 2009).
Various treatments for DM have been developed. Many of them aim to control blood glucose levels (Del Prato, 2009). Oral hypoglycemic agents are often used in patients with type 2 DM. Glucophage (metformin) is the most commonly used oral hypoglycemic agent (Kirpichnikov et al., 2002, Knowler et al., 2002). Interestingly, it has been shown recently that metformin increases Aβ expression in neuronal cultures (Chen et al., 2009). However, the effects of metformin on Aβ expression in diabetic mice are not reported. Its effects on other AD-like brain features, such as tau phosphorylation as well as learning and memory functions, in diabetic animals are not known. Thus, we designed this study to evaluate the AD-like brain functional and pathological changes and the effects of metformin on these changes in the db/db mice.
Section snippets
Materials and methods
The animal protocol was approved by the institutional Animal Care and Use Committee of the University of Virginia (Charlottesville, VA). All animal experiments were carried out in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publications number 80–23) revised in 1996.
Effects of metformin on the characteristics of type 2 DM in the db/db mice
The db/db mice start to have hyperglycemia at 3–4 weeks of age and develop a full spectrum of type 2 DM characteristics including obesity, hyperglycemia, hyperinsulinemia and insulin resistance by 8 weeks of age (Kim et al., 2009, Lin et al., 2000). As shown in Table 1, the db/db mice had a higher fasting blood glucose level and were heavier than the lean control mice when they were 6 weeks old (P < 0.001 and t(33) = 12.227 for the body weight comparison, P = 0.025 and t(44) = 2.326 for blood glucose
Discussion
It has been shown that there is a significant increase in the phospho-tau in the brains of mice and rats with type 1 and type 2 DM (Clodfelder-Miller et al., 2006, Kim et al., 2009, Li et al., 2007, Planel et al., 2007b). This phosphorylation occurs at multiple sites including Ser199, Ser202, Thr212, Thr231, Ser262 and Ser396 (Clodfelder-Miller et al., 2006, Kim et al., 2009, Li et al., 2007, Planel et al., 2007b). Obvious phosphorylation of tau starts as early as 10 days after streptozotocin
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
Acknowledgement
This study was supported by a grant (R01 GM065211 to Z Zuo) from the National Institutes of Health, Bethesda, Maryland, by a grant from the International Anesthesia Research Society (2007 Frontiers in Anesthesia Research Award to Z Zuo), Cleveland, Ohio, by a Grant-in-Aid from the American Heart Association Mid-Atlantic Affiliate (10GRNT3900019 to Z Zuo), Baltimore, Maryland, the Robert M. Epstein Professorship endowment, University of Virginia and a grant (81070912 to W Sheng) from National
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The research work was performed in and should be attributed to the Department of Anesthesiology, University of Virginia, Charlottesville, VA22908, USA.