title: Contribution of genetic and dietary insulin resistance to Alzheimer phenotype in APP/PS1 transgenic mice.
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.
authors.affiliation: Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland. mikko.hiltunen@uef.fi
authors.forename: Mikko
authors.initials: M
authors.lastname: Hiltunen
authors.forename: Vinoth K M
authors.initials: VK
authors.lastname: Khandelwal
authors.forename: Nagendra
authors.initials: N
authors.lastname: Yaluri
authors.forename: Tea
authors.initials: T
authors.lastname: Tiilikainen
authors.forename: Maija
authors.initials: M
authors.lastname: Tusa
authors.forename: Henna
authors.initials: H
authors.lastname: Koivisto
authors.forename: Marine
authors.initials: M
authors.lastname: Krzisch
authors.forename: Saila
authors.initials: S
authors.lastname: Vepsäläinen
authors.forename: Petra
authors.initials: P
authors.lastname: Mäkinen
authors.forename: Susanna
authors.initials: S
authors.lastname: Kemppainen
authors.forename: Pasi
authors.initials: P
authors.lastname: Miettinen
authors.forename: Annakaisa
authors.initials: A
authors.lastname: Haapasalo
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Heikki
authors.initials: H
authors.lastname: Tanila
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D005951:Glucose Tolerance Test; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006824:Hybridization, Genetic; D006943:Hyperglycemia / Q000235:genetics / Q000473:pathology; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000235:genetics*; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D053764:Presenilin-1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; D053764:Presenilin-1; D007335:Insulin-Like Growth Factor II; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3