[Fundamental study of memory impairment and non-cognitive behavioral alterations in APPswe/PS1dE9 mice].

In addition to cognitive decline, Alzheimer's disease patients also exhibit non-cognitive symptoms commonly referred to as behavioral and psychological symptoms of dementia, or BPSD. These symptoms have a serious impact on the quality of life of these patients, as well as that of their caregivers, but there are currently no effective therapies. The amyloid ß-peptide (Aß) is suspected to play a central role in the cascade leading to Alzheimer's disease, but the precise mechanisms are still incompletely known. To assess the influence of Aß pathology on cognitive and non-cognitive behaviors, we examined locomotor activity, motor coordination, and spatial memory in male and female APPswePS1dE9 mice (Alzheimer's disease model, double transgenic mice expressing an amyloid precursor protein with Swedish mutation and a presenilin-1 with deletion of exon 9) at 5 months of age, when the mice had subtle Aß deposits, and again at 9 months of age, when the mice had numerous Aß deposits. Compared to wild-type mice, the male and female APPswe/PS1dE9 mice showed normal motor coordination in the rotarod test at both 5 and 9 months. In the Morris water maze test, male and female APPswe/PS1dE9 mice showed impaired spatial memory at 9 months; however, no such deficits were found at 5 months. In a locomotor activity test, male APPswe/PS1dE9 mice exhibited locomotor hyperactivity at 9 months, while females exhibited locomotor hyperactivity at both 5 and 9 months compared to the control mice. Together, these results indicate that APPswe/PS1dE9 mice developed spatial memory impairment and BPSD-like behavioral alterations resulting from Aß accumulation.

Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes.

BACKGROUND: Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity. METHODS: Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF) rats. RESULTS: In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity. CONCLUSIONS: Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.

Analysis of the effect of canagliflozin on renal glucose reabsorption and progression of hyperglycemia in zucker diabetic Fatty rats.

Sodium-glucose cotransporter 2 (SGLT2) plays a major role in renal glucose reabsorption. To analyze the potential of insulin-independent blood glucose control, the effects of the novel SGLT2 inhibitor canagliflozin on renal glucose reabsorption and the progression of hyperglycemia were analyzed in Zucker diabetic fatty (ZDF) rats. The transporter activity of recombinant human and rat SGLT2 was inhibited by canagliflozin, with 150- to 12,000-fold selectivity over other glucose transporters. Moreover, in vivo treatment with canagliflozin induced glucosuria in mice, rats, and dogs in a dose-dependent manner. It inhibited apparent glucose reabsorption by 55% in normoglycemic rats and by 94% in hyperglycemic rats. The inhibition of glucose reabsorption markedly reduced hyperglycemia in ZDF rats but did not induce hypoglycemia in normoglycemic animals. The change in urinary glucose excretion should not be used as a marker to predict the glycemic effects of this SGLT2 inhibitor. In ZDF rats, plasma glucose and HbA1c levels progressively increased with age, and pancreatic ß-cell failure developed at 13 weeks of age. Treatment with canagliflozin for 8 weeks from the prediabetic stage suppressed the progression of hyperglycemia, prevented the decrease in plasma insulin levels, increased pancreatic insulin contents, and minimized the deterioration of islet structure. These results indicate that selective inhibition of SGLT2 with canagliflozin controls the progression of hyperglycemia by inhibiting renal glucose reabsorption in ZDF rats. In addition, the preservation of ß-cell function suggests that canagliflozin treatment reduces glucose toxicity via an insulin-independent mechanism.

MGAT2 deficiency ameliorates high-fat diet-induced obesity and insulin resistance by inhibiting intestinal fat absorption in mice.

BACKGROUND: Resynthesis of triglycerides in enterocytes of the small intestine plays a critical role in the absorption of dietary fat. Acyl-CoA:monoacylglycerol acyltransferase-2 (MGAT2) is highly expressed in the small intestine and catalyzes the synthesis of diacylglycerol from monoacylglycerol and acyl-CoA. To determine the physiological importance of MGAT2 in metabolic disorders and lipid metabolism in the small intestine, we constructed and analyzed Mgat2-deficient mice. RESULTS: In oral fat tolerance test (OFTT), Mgat2-deficient mice absorbed less fat into the circulation. When maintained on a high-fat diet (HFD), Mgat2-deficient mice were protected from HFD-induced obesity and insulin resistance. Heterozygote (Mgat2+/-) mice had an intermediate phenotype between Mgat2+/+ and Mgat2-/- and were partially protected from metabolic disorders. Despite of a decrease in fat absorption in the Mgat2-deficient mice, lipid levels in the feces and small intestine were comparable among the genotypes. Oxygen consumption was increased in the Mgat2-deficient mice when maintained on an HFD. A prominent upregulation of the genes involved in fatty acid oxidation was observed in the duodenum but not in the liver of the Mgat2-deficient mice. CONCLUSION: These results suggest that MGAT2 has a pivotal role in lipid metabolism in the small intestine, and the inhibition of MGAT2 activity may be a promising strategy for the treatment of obesity-related metabolic disorders.

Differential regulation of neurogenesis in two neurogenic regions of APPswe/PS1dE9 transgenic mice.

Neurogenesis occurs in two neurogenic regions of the adult mammalian brain: the subgranular zone and the subventricular zone. We have recently demonstrated that the number of bromodeoxyuridine-positive and doublecortin-positive cells is decreased in the subgranular zone of amyloid precursor protein with a Swedish mutation and presenilin-1 with a deletion of exon 9 transgenic mice, an animal model of Alzheimer's disease. In this study, we characterized neurogenesis in the subventricular zone of amyloid precursor protein with a Swedish mutation and presenilin-1 with a deletion of exon 9 transgenic mice at 9 months of age and compared it with neurogenesis in the subgranular zone. In the subventricular zone, the number of proliferating cell nuclear antigen-positive and bromodeoxyuridine-positive cells were normal. In the subgranular zone, the number of proliferating cell nuclear antigen-positive cells was normal; however, the number of bromodeoxyuridine-positive cells was significantly decreased. These results suggest that neurogenesis, probably reflecting the survival of neural progenitor cells, differs between the subgranular zone and the subventricular zone.

Decreased proliferation of hippocampal progenitor cells in APPswe/PS1dE9 transgenic mice.

A recent hypothesis suggests that there is impaired hippocampal neurogenesis in Alzheimer's disease. Here we examined the proliferation, the first stage in neurogenesis, of hippocampal progenitor cells in amyloid precursor protein with Swedish mutation and presenilin-1 with deletion of exon 9 (APPswe/PS1dE9) transgenic mice. Compared with age-matched wild-type mice, transgenic mice at 5 months of age with low amyloid beta-peptide (Abeta) levels and subtle Abeta deposits showed normal proliferation of hippocampal progenitor cells; however, transgenic mice at 9 months of age with high Abeta levels and numerous Abeta deposits showed decreased proliferation of these cells. The number of proliferating cells in male transgenic mice was indistinguishable from that in female transgenic mice. These results indicate that neurogenesis is decreased with degrees of Abeta pathology, and that there is no gender difference in their proliferation in APPswe/PS1dE9 transgenic mice.