title: Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer's disease.
abstract: Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-transgenic (3xTg)-AD mouse model of AD, compared with those in nontransgenic (non-Tg) controls, at 6, 8, and 14 mo of age. We found a more pronounced cortical Aβ accumulation (2- and 3.5-fold increase in Aβ42 in the soluble and insoluble protein fractions, respectively) in female 3xTg-AD mice than in the males. Furthermore, female 3xTg-AD mice displayed a significant deterioration in glucose tolerance (AUC, +118% vs. non-Tg mice at 14 mo). Fasting plasma insulin levels rose 2.5-fold from 6 to 14 mo of age in female 3xTg-AD mice. Glucose intolerance and cortical amyloid pathology worsened with age, and both were more pronounced in the females. Pancreatic amyloidopathy was revealed and could underlie the observed deficit in glycemic response in 3xTg-AD mice. The present results suggest that AD-like neuropathology extends to the pancreas in the 3xTg-AD mouse, leading to glucose intolerance and contributing to a pathologic self-amplifying loop between AD and T2D.
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Milene
authors.initials: M
authors.lastname: Vandal
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: White
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chevrier
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Cyntia
authors.initials: C
authors.lastname: Tremblay
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: St-Amour
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Planel
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Andre
authors.initials: A
authors.lastname: Marette
authors.affiliation: *Faculté de Pharmacie, Institut des Nutraceutiques et des Aliments Fonctionnels, and Département de Medicine, Axe de Cardiologie, Faculté de Médicine, Université Laval, Québec, Québec, Canada; Axe Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université Laval (CHUL), Québec, Québec, Canada; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, North Carolina, USA; and Institut Universitaire de Pneumologie et de Cardiologie, Québec, Québec, Canada.
authors.forename: Frederic
authors.initials: F
authors.lastname: Calon
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018149:Glucose Intolerance / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000097:blood*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010446:Peptide Fragments / Q000378:metabolism; D012737:Sex Factors
chemical_list: D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D007328:Insulin; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: amyloid; insulin; pancreas