University of Kuopio

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Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice.

Mikko Hiltunen; Vinoth K M Khandelwal; Nagendra Yaluri; Tea Tiilikainen; Maija Tusa; Henna Koivisto; Marine Krzisch; Saila Vepsäläinen; Petra Mäkinen; Susanna Kemppainen; et al. (Profiled Author: Soininen, Hilkka)

Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland. mikko.hiltunen@uef.fi
Journal of cellular and molecular medicine 2012;16(6):1206-22.

According to epidemiological studies, type-2 diabetes increases the risk of Alzheimer's disease. Here, we induced hyperglycaemia in mice overexpressing mutant amyloid precursor protein and presenilin-1 (APdE9) either by cross-breeding them with pancreatic insulin-like growth factor 2 (IGF-2) overexpressing mice or by feeding them with high-fat diet. Glucose and insulin tolerance tests revealed significant hyperglycaemia in mice overexpressing IGF-2, which was exacerbated by high-fat diet. However, sustained hyperinsulinaemia and insulin resistance were observed only in mice co-expressing IGF-2 and APdE9 without correlation to insulin levels in brain. In behavioural tests in aged mice, APdE9 was associated with poor spatial learning and the combination of IGF-2 and high-fat diet further impaired learning. Neither high-fat diet nor IGF-2 increased β-amyloid burden in the brain. In male mice, IGF-2 increased β-amyloid 42/40 ratio, which correlated with poor spatial learning. In contrast, inhibitory phosphorylation of glycogen synthase kinase 3β, which correlated with good spatial learning, was increased in APdE9 and IGF-2 female mice on standard diet, but not on high-fat diet. Interestingly, high-fat diet altered τ isoform expression and increased phosphorylation of τ at Ser202 site in female mice regardless of genotype. These findings provide evidence for new regulatory mechanisms that link type-2 diabetes and Alzheimer pathology.

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