Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice |
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Authors: | Mikko Hiltunen Vinoth K M Khandelwal Nagendra Yaluri Tea Tiilikainen Maija Tusa Henna Koivisto Marine Krzisch Saila Vepsäläinen Petra Mäkinen Susanna Kemppainen Pasi Miettinen Annakaisa Haapasalo Hilkka Soininen Markku Laakso Heikki Tanila |
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Institution: | 1. Institute of Clinical Medicine – Neurology, University of Eastern Finland, Kuopio, Finland;2. School of Pharmacy, University of Eastern Finland, Kuopio, Finland;3. Institute of Clinical Medicine – Medicine, University of Eastern Finland, Kuopio, Finland;4. A. I. Virtanen Institute, University of Eastern Finland, Kuopio, Finland;5. Department of Medicine, Kuopio University Hospital, Kuopio, Finland;6. Department of Neurology, Kuopio University Hospital, Kuopio, Finland |
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Abstract: | 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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Keywords: | Alzheimer’ s disease β ‐amyloid hyperinsulinaemia insulin growth factor 2 insulin resistance type‐2 diabetes mellitus |
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