title: Glucose tolerance and insulin sensitivity are impaired in APP/PS1 transgenic mice prior to amyloid plaque pathogenesis and cognitive decline.
abstract: Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by beta-amyloid (Aβ) deposition, neurofibrillary tangles and cognitive decline. Clinical data suggests that both type 1 and type 2 diabetes are risk factors for AD-related dementia and several clinical studies have demonstrated that AD patients show alterations in peripheral glucose regulation characterized by insulin resistance (hyperinsulinemia) or hypoinsulinemia. Whether animal models of AD exhibit a pre-diabetic phenotype without additional dietary or experimental manipulation is unclear however, with contradictory data available. Further, most studies have not examined the time course of potential pre-diabetic changes relative to AD pathogenesis and cognitive decline. Thus, in this study we tested the hypothesis that a pre-diabetic phenotype (peripheral metabolic dysregulation) exists in the APP/PS1 transgenic model of AD under normal conditions and precedes AD-related pathology. Specifically, we examined glucose tolerance in male APP/PS1 mice on a C57BL/6J congenic background at 2, 4-6 and 8-9months of age by assessing fasting glucose levels, glucose tolerance, plasma insulin levels and insulin sensitivity as well as the development of pathological characteristics of AD and verified that our APP/PS1 mice develop cognitive impairment. Here we show that APP/PS1 mice, compared to wild-type controls, exhibit a significant impairment in glucose tolerance during an intraperitoneal glucose tolerance test (ipGTT) and a trend for increased fasting plasma insulin concentrations as early as 2months of age, while extracellular Aβ1-42deposition occurs later and cognitive decline exists at 8-9months of age. Moreover, APP/PS1 mice did not respond as well to exogenous insulin as the wild-type controls during an intraperitoneal insulin tolerance test (ipITT). Taken together, these data reveal that male APP/PS1 mice on a C57BL/6J congenic background exhibit a pre-diabetic phenotype prior to the development of AD-like pathology and that this metabolic deficit persists when they exhibit neuropathology and cognitive decline. This raises the question of whether altered glucose regulation and insulin production/secretion could contribute to AD pathogenesis.
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL 62901, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Macklin
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL 62901, USA.
authors.forename: Chelsea M
authors.initials: CM
authors.lastname: Griffith
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL 62901, USA; Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL 62901, USA.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Rose
authors.affiliation: Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL 62901, USA; Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan 410013, China.
authors.forename: Xiao-Xin
authors.initials: XX
authors.lastname: Yan
authors.affiliation: Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL 62901, USA; Center for Integrated Research in Cognitive and Neural Sciences, Southern Illinois University, Carbondale, IL 62901, USA. Electronic address: ppatrylo@siumed.edu.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Patrylo
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D060825:Cognitive Dysfunction / Q000097:blood*; D004195:Disease Models, Animal; D005951:Glucose Tolerance Test; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D001786:Blood Glucose; D007328:Insulin; D053764:Presenilin-1; C580804:presenilin 1, mouse
keywords: Alzheimer's disease; Hippocampus; Morris water maze; Pre-diabetic