title: Progressive Neuronal Pathology and Synaptic Loss Induced by Prediabetes and Type 2 Diabetes in a Mouse Model of Alzheimer's Disease.
abstract: Age remains the main risk factor for developing Alzheimer's disease (AD) although certain metabolic alterations, including prediabetes and type 2 diabetes (T2D), may also increase this risk. In order to understand this relationship, we have studied an AD-prediabetes mouse model (APP/PS1) with severe hyperinsulinemia induced by long-term high fat diet (HFD), and an AD-T2D model, generated by crossing APP/PS1 and db/db mice (APP/PS1xdb/db). In both, prediabetic and diabetic AD mice, we have analyzed underlying neuronal pathology and synaptic loss. At 26 weeks of age, when both pathologies were clearly established, we observed severe brain atrophy in APP/PS1xdb/db animals as well as cortical thinning, accompanied by increased caspase activity. Reduced senile plaque burden and elevated soluble Aβ40 and 42 levels were observed in AD-T2D mice. Further assessment revealed a significant increase of neurite curvature in prediabetic-AD mice, and this effect was worsened in AD-T2D animals. Synaptic density loss, analyzed by array tomography, revealed a synergistic effect between T2D and AD, whereas an intermediate state was observed, once more, in prediabetic-AD mice. Altogether, our data suggest that early prediabetic hyperinsulinemia may exacerbate AD pathology, and that fully established T2D clearly worsens these effects. Therefore, it is feasible that early detection of prediabetic state and strict metabolic control could slow or delay progression of AD-associated neuropathological features.
authors.affiliation: Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Ramos-Rodriguez
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Spires-Jones
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.|Institute of Psychiatry, Psychology & Neuroscience, Department of Basic and Clinical Neuroscience, King's College London, London, UK.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Pooler
authors.affiliation: Department of Pediatrics, School of Medicine, Universidad de Cadiz, Cadiz, Spain.
authors.forename: Alfonso Maria
authors.initials: AM
authors.lastname: Lechuga-Sancho
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bacskai
authors.affiliation: Division of Physiology, School of Medicine, Universidad de Cadiz, Cadiz, Spain. monica.garcia@uca.es.
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001284:Atrophy / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D008822:Mice, Transgenic; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011236:Prediabetic State / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D053764:Presenilin-1 / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology*
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D020169:Caspases
keywords: Alzheimer’s disease; Array tomography; Axonal curvature; Hyperinsulinemia; Synaptic density; Type 2 diabetes