title: Prediabetes-induced vascular alterations exacerbate central pathology in APPswe/PS1dE9 mice.
abstract: Age remains the main risk factor for developing Alzheimer's disease (AD) although certain metabolic alterations, including prediabetes and hyperinsulinemia, also increase this risk. We present a mouse model of AD (APPswe/PS1dE9 mouse) with severe hyperinsulinemia induced by long-term high fat diet (HFD) treatment. After 23 weeks on HFD learning and memory processes were compromised. We observed a significant increase in tau hyperphosphorylation and Aβ pathology, including Aβ levels and amyloid burden. Microglia activation was also significantly increased in HFD-treated mice, both in close proximity to and far from senile plaques. Insulin degrading enzyme and neprilysin levels were not affected, suggesting that Aβ degradation pathways were preserved, whereas we detected an increase in spontaneous cortical bleeding that could underlay an impairment of Aβ interstitial fluid drainage, contributing to the increase in Aβ deposition in APP/PS1-HFD mice. Altogether our data suggest that early hyperinsulinemia is enough to exacerbate AD pathology observed in APP/PS1 mice, and supports the role of insulin-resistance therapies to stop or delay central complications associated.
authors.affiliation: Division of Physiology, School of Medicine, University of Cadiz, Cadiz 11003, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Ramos-Rodriguez
authors.affiliation: Division of Physiology, School of Medicine, University of Cadiz, Cadiz 11003, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Ortiz-Barajas
authors.affiliation: Division of Physiology, School of Medicine, University of Cadiz, Cadiz 11003, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Gamero-Carrasco
authors.affiliation: Division of Physiology, School of Medicine, University of Cadiz, Cadiz 11003, Spain.
authors.forename: Pablo Romero
authors.initials: PR
authors.lastname: de la Rosa
authors.affiliation: Division of Physiology, School of Medicine, University of Cadiz, Cadiz 11003, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Infante-Garcia
authors.affiliation: Service of Clinical Analyses, University Hospital Puerta del Mar of Cadiz, Cadiz 11009, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Zopeque-Garcia
authors.affiliation: Department of Paediatrics, School of Medicine, University of Cadiz, Cadiz 11003, Spain.
authors.forename: Alfonso M
authors.initials: AM
authors.lastname: Lechuga-Sancho
authors.affiliation: Division of Physiology, School of Medicine, University of Cadiz, Cadiz 11003, Spain. Electronic address: monica.garcia@uca.es.
authors.forename: Monica
authors.initials: M
authors.lastname: Garcia-Alloza
mesh_terms: D000544:Alzheimer Disease / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D006946:Hyperinsulinism / Q000209:etiology / Q000378:metabolism; D007333:Insulin Resistance; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D011236:Prediabetic State / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology*; D053764:Presenilin-1 / Q000235:genetics*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; C580804:presenilin 1, mouse; D016875:tau Proteins
keywords: Alzheimer's disease; Amyloid-β; Haemorrhage; Hyperinsulinemia; Insulin degrading enzyme; Microglia; Neprilysin; Prediabetes; Tau