Differential central pathology and cognitive impairment in pre-diabetic and diabetic mice
Introduction
Progressive increase of life expectancy is secondarily contributing to a significant increase in aging associated pathologies, among which Alzheimer's disease (AD) and vascular dementia (VD) are of special relevance, since these are the most common causes of dementia in elderly people. The most prominent neuropathological features of AD are the presence of senile plaques, composed of amyloid-Ī² peptides, neurofibrillary tangles, primarily composed of abnormally phosphorylated tau, and synaptic loss and brain atrophy (Hyman and Gomez-Isla, 1997). VD is a heterogeneous pathology that ranges from multiple microinfarcts or small vessel ischemic disease, to vascular damage (Craft, 2009). The picture gets more complicated since borderlines between AD and VD are often blurry, and in many patients markers of vascular injury coexist with traditional AD hallmarks (Craft, 2009). On the other hand, the underlying mechanisms are not completely understood and although age remains the main risk factor to suffer dementia, there are other factors that may predispose to suffer AD and VD. In this sense, type 2 diabetes mellitus (T2D) might also play a relevant role in the onset and development of dementia. T2D is a metabolic disorder primarily characterized by insulin resistance and hyperglycemia, and as T2D evolves, other associated pathologies appear, including micro and macrovascular complications and peripheral neuropathy (Kim and Feldman, 2012). Moreover clinical studies suggest that T2D might be a risk factor to suffer AD and VD (Ott et al., 1996, Luchsinger et al., 2004, Plastino et al., 2010).
The close relationship between T2D and dementia has lead to many recent revisions of the field (Kuljis and Salkovic-Petrisic, 2011, de la Monte, 2012) as well as in epidemiological studies (Ott et al., 1996, Craft et al., 2003, Schrijvers et al., 2010, Chen et al., 2011). Moreover a recent study has related specific polymorphism of AMP-activated protein kinase concomitantly to dementia and diabetes (Kim et al., 2012). This relationship has even lead to the identification of a new complex syndrome: type 3 diabetes (de la Monte et al., 2006). However there are still limited studies focusing on the underlying mechanisms (Ho et al., 2004, Bomfim et al., 2012), and only recently animal models harboring both T2D and AD have been developed (Takeda et al., 2010, Hiltunen et al., 2012, Jimenez-Palomares et al., 2012). The diabetic db/db mouse (leptin receptor KO mouse) (Hummel et al., 1966) is a useful model of T2D that results in excessive food consumption, precocious and progressive increase in body weight, hyperglycemia and hyperinsulinemia. Although db/db mice have been profusely used as metabolic syndrome and T2D model, central nervous system (CNS) complications as well as learning and memory alterations derived from diabetes and associated comorbidities observed in this model such as obesity or dyslipidemia, have only been partially characterized in this mouse model. On the other hand whether severe diabetes or just early hyperinsulinemia can induce CNS alterations remains controversial and observations seem to depend on the experimental approach to induce hyperinsulinemia and the specific tests performed afterwards (Arvanitidis et al., 2009, Camargo et al., 2012, Heyward et al., 2012).
The aim of our study was to analyze AD- and VD-related features in the CNS of db/db mice, characterized by long-term insulin resistance and diabetes, as well as associated comorbidities, and secondarily, in a diet-induced model of insulin resistance and hyperinsulinemia. db/db mice exhibited pathological characteristics that mimic both AD and VD, including age-dependent cognitive deterioration as well as brain atrophy, increased presence of spontaneous hemorrhages and increased tau phosphorylation. These alterations preferentially affected cortical regions and were of special relevance once the diabetic process has been established, since a high fat diet (HFD)-induced incipient hyperinsulinemia in C57Bl6 mice only produced mild CNS alterations. Interestingly, metabolic parameters measured in db/db mice, including glucose and insulin levels turned up to be reliable predictors of both, memory impairment as well as cortical atrophy and presence of spontaneous hemorrhages.
Section snippets
Animals
The mouse model of obesity and type 2 diabetes used in this study is the db/db mouse. The introduction of an RsaI site by the Leprdb mutation in the leptin receptor gene was detected by 126 PCR as previously described (Jimenez-Palomares et al., 2012). C57BL/KsJ heterozygous db/+ mice were purchased from Harlan Laboratories (Boxmeer, The Netherlands). WT, db/db and db/+ mice were generated from crosses between heterozygous db/+ mice. Animals were aged up to 4, 14 and 26 weeks of age and 7ā16
Metabolic parameters and T2D progression in db/db and HFD mice
db/db mice developed hyperinsulinemia and T2D with age, as previously described (Hummel et al., 1966). At 4 weeks of age db/db mice showed severe hyperinsulinemia, although body weight and glucose levels were still similar to control values (Table 1). By the age of 14 weeks, T2D was fully established in db/db mice, with glucose levels above 300Ā mg/dl (Jimenez-Palomares et al., 2012) and body weights significantly higher than those measured in control mice. Although still hyperinsulinemic, high
Discussion
Although many clinical and epidemiological studies have suggested a close relationship between type 1 diabetes (Cooray et al., 2008), and more robustly T2D and dementia (Ott et al., 1996, Luchsinger et al., 2004, Plastino et al., 2010, Schrijvers et al., 2010) it remains difficult in basic research studies to elucidate the mechanisms underlying this relationship (Takeda et al., 2010, Bomfim et al., 2012, Hiltunen et al., 2012, Jimenez-Palomares et al., 2012). In this study we have used a
Role of the funding sources
M.G.-A. was supported by Ramon y Cajal program RYC-2008-02333, ISCIII ā Ministerio de EconomĆa y Competitividad, Spain. Junta de Andalucia, Proyectos de InvestigaciĆ³n de Excelencia (P11-CTS-7847), Instituto de Salud Carlos III and FEDER (European Union), cofinanced by Fondo Europeo de Desarrollo Regional āUna manera de hacer Europaā PI12/00675 (Monica Garcia-Alloza). I.C.-C. was supported by RYC-2011-08101, ISCIII-SubdirecciĆ³n General de EvaluaciĆ³n y Fomento de la InvestigaciĆ³n, Spain (
Conflict of interest
All authors have nothing to declare.
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