Insulin resistance and Alzheimer's disease pathogenesis: Potential mechanisms and implications for treatment
ABSTRACT Insulin modulates cognition and other aspects of normal brain function. Insulin resistance is characterized by chronic peripheral insulin elevations, and it is accompanied by reduced brain insulin levels and insulin activity. Obesity, type 2 diabetes mellitus and hypertension are strongly associated with insulin resistance. In addition, insulin resistance increases the risk of age-related memory impairment and Alzheimer's disease. Possible mechanisms through which these risks are increased include the effects of peripheral hyperinsulinemia on memory, CNS inflammation, and regulation of the beta-amyloid peptide. We have shown that raising plasma insulin in humans to levels that characterize patients with insulin resistance increases the levels of Abeta and inflammatory agents in brain. These convergent effects may impair memory and induce AD pathology. Therapeutic strategies focused on preventing or correcting insulin abnormalities may thus benefit a subset of adults with age-related memory impairment and AD.
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ABSTRACT: Alzheimer's disease (AD) is a progressive and degenerative disorder accompanied by cognitive impairment, but effective strategies against AD are currently not available. Interestingly, glucagon-like peptide-1 (GLP-1) used in type 2 diabetes mellitus (T2DM) have shown neuroprotective effects in preclinical studies of AD. Lixisenatide, an effective GLP-1 receptor agonist with much longer half life than GLP-1, has been licensed in the EU as a treatment for T2DM. However, the neuroprotective effects of lixisenatide in the brain remain to be clarified. In the present study, we report for the first time the effects of lixisenatide on the amyloid β (Aβ) protein-induced impairments in spatial learning and memory of rats, and investigated its electrophysiological and molecular mechanisms. We found that: (1) bilateral intrahippocampal injection of Aβ25-35 resulted in a significant decline in spatial learning and memory of rats, as well as a suppression of in vivo hippocampal long-term potentiation (LTP); (2) lixisenatide treatment effectively prevented the Aβ25-35-induced impairments; (3) lixisenatide inhibited the Aβ25-35 injection-induced activation of glycogen synthase kinase 3β (GSK3β), with a significant increase in phosphorylation of ser9 and a significant decrease in phosphorylation of Y216. These results indicate that lixisenatide, by affecting the PI3K-Akt-GSK3β pathway, can prevent Aβ-related impairments in synaptic plasticity and spatial memory of rats, suggesting that lixisenatide may be a novel and effective treatment for AD.Neuroscience 02/2014; 277. DOI:10.1016/j.neuroscience.2014.02.022 · 3.33 Impact Factor
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ABSTRACT: A study was conducted to assess the physiopathological significance of sirtuin 6 (SIRT6) at the brain cortical level. We analyzed the specific expression and subcellular localization of SIRT6 in young db/db mice, an experimental animal model of type II Diabetes mellitus. We analyzed the cytoarchitecture of the brain cortex, evaluated SIRT6 expression and its localization by immunohistochemistry comparing db/db mice to lean control mice, examining the six cortical layers and the motor and somatosensory cortex. Finally, we calculated a SIRT6 labeling index. We observed the absence of significant morphological differences between lean and db/db mice, indicating that young db/db mice showed a neuronal morphology and distribution similar to that of lean mice and also normal brain tissue architecture with intact cortical layers. Moreover, sirtuin 6 is mainly localized in the nucleus of both lean and db/db mice. In particular, the db/db mice showed few positive cells compared to lean control mice in all cortical layers. We found a lower sirtuin 6 labeling index without significant differences between the motor and somatosensory cortex. Our findings contribute to further understanding the sirtuin 6 immunohistochemical changes in the early stages of type II Diabetes mellitus and propose its possible implication in the pathogenic processes associated with Diabetes mellitus and diabetes-induced neurodegeneration.Acta histochemica 09/2013; DOI:10.1016/j.acthis.2013.08.006 · 1.76 Impact Factor
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ABSTRACT: Type 2 diabetes is a risk factor in the development of Alzheimer's disease (AD). It has been shown that insulin signalling is desensitised in the brains of AD patients. The incretin hormone Glucagon-like peptide-1 (GLP-1) facilitates insulin signalling, and long-lasting analogues such as liraglutide (Victoza®) are on the market as type 2 diabetes treatments. We have previously shown that liraglutide improved cognitive function, reduced amyloid plaque deposition, inflammation, overall APP and oligomer levels and enhanced LTP when injected peripherally for two months in 7 month old APPswe/PS1ΔE9 (APP/PS1) mice. This showed that liraglutide has preventive effects at the early stage of AD development. The current study investigated whether Liraglutide would have restorative effects in late-stage Alzheimer's disease in mice. Accordingly, 14-Month-old APP/PS1 and littermate control mice were injected with Liraglutide (25nmol/kg bw) ip. for 2 months. Spatial memory was improved by Liraglutide-treatment in APP/PS1 mice compared with APP/PS1 saline-treated mice. Overall plaque load was reduced by 33%, and inflammation reduced by 30%, while neuronal progenitor cell count in the dentate gyrus was increased by 50%. LTP was significantly enhanced in APP/PS1 liraglutide-treated mice compared with APP/PS1 saline mice, corroborated with increased synapse numbers in hippocampus and cortex. Total brain APP and beta-amyloid oligomer levels were reduced in Liraglutide-treated APP/PS1 mice while IDE levels were increased. These results demonstrate that Liraglutide not only has preventive properties, but can reverse some of the key pathological hallmarks of AD. Liraglutide is now being tested in clinical trials in AD patients.Neuropharmacology 08/2013; DOI:10.1016/j.neuropharm.2013.08.005 · 4.82 Impact Factor