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Calon F.,Laval University | Calon F.,Center Hospitalier Of Luniversite Laval Chul Research Center
Current Alzheimer Research | Year: 2011

The current rise in the prevalence of Alzheimer's disease (AD) is unfortunately not matched by new treatment options. In the last 10 years, epidemiological, preclinical and clinical data have enlightened the possible preventive action of omega-3 polyunsaturated fatty acids (n-3 PUFA) in AD and other diseases. While the contribution of recent studies to our general knowledge is priceless, many important new questions have been raised. In the present review, we aim at addressing some of these timely interrogations. First, the transport of n-3 PUFA across the blood-brain barrier is underscored based on preclinical data. Second, the relative contribution of two neuroactive n-3 PUFA found in fish oil, docosa-hexaenoic acid (DHA; 22:6 n-3) and eicosapentaenoic acid (EPA, 20:5 n-3), remains unclear and is reviewed. Third, clinical trials on neurodegenerative diseases consistently remind us that treating early is critical, and this is likely to be the case with n-3 PUFA in AD as well. Fourth, we draw attention to the possibility that the current knowledge translation approach to make health recommendations might have to be adapted to non-patentable endogenous compounds like n-3 PUFA. We propose that answers to these critical questions will be instrumental toward a rational use of n-3 PUFA in AD. © 2011 Bentham Science Publishers Ltd. Source

Couture P.,Institute of Nutrition and Functional Foods | Couture P.,Proteomic Center | Tremblay A.J.,Institute of Nutrition and Functional Foods | Tremblay A.J.,Proteomic Center | And 4 more authors.
Journal of Lipid Research | Year: 2014

Insulin resistance (IR) is associated with elevated plasma levels of triglyceride-rich lipoproteins (TRLs) of intestinal origin. However, the mechanisms underlying the overaccumulation of apolipoprotein (apo)B-48-containing TRLs in individuals with IR are not yet fully understood. This study examined the relationships between apoB-48- containing TRL kinetics and the expression of key intestinal genes and proteins involved in lipid/lipoprotein metabolism in 14 obese nondiabetic men with IR compared with 10 insulin-sensitive (IS) men matched for waist circumference. The in vivo kinetics of TRL apoB-48 were assessed using a primed-constant infusion of L-[5,5,5-D 3 ]leucine for 12 h with the participants in a constantly fed state. The expression of key intestinal genes and proteins involved in lipid/ lipoprotein metabolism was assessed by performing realtime PCR quantifi cation and LC-MS/MS on duodenal biopsy specimens. The TRL apoB-48 pool size and production rate were 102% ( P < 0.0001) and 87% ( P = 0.01) greater, respectively, in the men with IR versus the IS men. On the other hand, intestinal mRNA levels of sterol regulatory element binding factor-2, hepatocyte nuclear factor-4 - , and microsomal triglyceride transfer protein were signifi cantly lower in the men with IR than in the IS men. These data indicate that IR is associated with intestinal overproduction of lipoproteins and signifi cant downregulation of key intestinal genes involved in lipid/lipoprotein metabolism. Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc. Source

Tremblay A.J.,Center Hospitalier Of Luniversite Laval Chul Research Center | Tremblay A.J.,Laval University | Lamarche B.,Laval University | Kelly I.,Proteomic Center | And 5 more authors.
Diabetes, Obesity and Metabolism | Year: 2014

Aim: To investigate the effects of sitagliptin therapy on the kinetics of triglyceride-rich lipoprotein (TRL) apolipoprotein (apo)B-48, VLDL apoB-100, apoE and apoC-III in patients with type 2 diabetes. Methods: Twenty-two subjects with type 2 diabetes were recruited in this double-blind crossover study, during which the subjects received sitagliptin (100 mg/day) or placebo for a 6-week period each. At the end of each phase of treatment, the in vivo kinetics of the different apolipoproteins were assessed using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h, with the participants in a constantly fed state. Results: Sitagliptin therapy significantly reduced fasting plasma triglyceride (-15.4%, p = 0.03), apoB-48 (-16.3%, p = 0.03) and free fatty acid concentrations (-9.5%, p = 0.04), as well as plasma HbA1c (placebo: 7.0% ± 0.8 vs. sitagliptin: 6.6% ± 0.7, p < 0.0001) and plasma glucose levels (-13.5%, p = 0.001), without any significant effect on insulin levels. Kinetic results showed that treatment with sitagliptin significantly reduced the pool size of TRL apoB-48 by -20.8% (p = 0.03), paralleled by a reduction in the production rate of these particles (-16.0%, p = 0.03). The VLDL apoB-100 pool size was also significantly decreased by sitagliptin therapy (-9.3%, p = 0.03), mainly because of a reduction in the hepatic secretion of these lipoproteins, although this difference did not reach statistical significance (-9.2%, p = 0.06). Conclusions: Treatment with sitagliptin for 6 weeks reduced triglyceride-rich apoB-containing lipoprotein levels by reducing the synthesis of these particles. © 2014 John Wiley & Sons Ltd. Source

Paris-Robidas S.,Laval University | Paris-Robidas S.,Center Hospitalier Of Luniversite Laval Chul Research Center | Brochu E.,Laval University | Brochu E.,Center Hospitalier Of Luniversite Laval Chul Research Center | And 18 more authors.
Brain | Year: 2012

The development of new treatments for essential tremor, the most frequent movement disorder, is limited by a poor understanding of its pathophysiology and the relative paucity of clinicopathological studies. Here, we report a post-mortem decrease in GABAA (35 reduction) and GABAB (22-31 reduction) receptors in the dentate nucleus of the cerebellum from individuals with essential tremor, compared with controls or individuals with Parkinson's disease, as assessed by receptor-binding autoradiography. Concentrations of GABAB receptors in the dentate nucleus were inversely correlated with the duration of essential tremor symptoms (r2=0.44, P<0.05), suggesting that the loss of GABAB receptors follows the progression of the disease. In situ hybridization experiments also revealed a diminution of GABAB(1a+b) receptor messenger RNA in essential tremor (↓27). In contrast, no significant changes of GABAA and GABAB receptors (protein and messenger RNA), GluN2B receptors, cytochrome oxidase-1 or GABA concentrations were detected in molecular or granular layers of the cerebellar cortex. It is proposed that a decrease in GABA receptors in the dentate nucleus results in disinhibition of cerebellar pacemaker output activity, propagating along the cerebello-thalamo- cortical pathways to generate tremors. Correction of such defective cerebellar GABAergic drive could have a therapeutic effect in essential tremor. © 2011 The Author. Source

Julien C.,Laval University | Julien C.,Center Hospitalier Of Luniversite Laval Chul Research Center | Tremblay C.,Laval University | Tremblay C.,Center Hospitalier Of Luniversite Laval Chul Research Center | And 8 more authors.
Neurobiology of Aging | Year: 2010

To investigate potential dietary risk factors of Alzheimer's disease (AD), triple transgenic (3xTg-AD) mice were exposed from 4 to 13 months of age to diets with a low n-3:n-6 polyunsaturated fatty acid (PUFA) ratio incorporated in either low-fat (5% w/w) or high-fat (35% w/w) formulas and compared with a control diet. The n-3:n-6 PUFA ratio was decreased independently of the dietary treatments in the frontal cortex of 3xTg-AD mice compared to non-transgenic littermates. Consumption of a high-fat diet with a low n-3:n-6 PUFA ratio increased amyloid-β (Aβ) 40 and 42 concentrations in detergent-insoluble extracts of parieto-temporal cortex homogenates from 3xTg-AD mice. Low n-3:n-6 PUFA intake ratio increased insoluble tau regardless of total fat consumption, whereas high-fat diet incorporating a low n-3:n-6 PUFA ratio also increased soluble tau compared to controls. Moreover, the high-fat diet decreased cortical levels of the postsynaptic marker drebrin, while leaving presynaptic proteins synaptophysin, SNAP-25 and syntaxin 3 unchanged. Overall, these results suggest that high-fat consumption combined with low n-3 PUFA intake promote AD-like neuropathology. © 2008 Elsevier Inc. Source

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