title: Hypercholesterolemia induces short-term spatial memory impairments in mice: up-regulation of acetylcholinesterase activity as an early and causal event?
abstract: Epidemiological studies have indicated hypercholesterolemia in midlife as a risk factor for dementia in later life, bringing cholesterol to the forefront of Alzheimer's disease research. Herein, we modeled mild hypercholesterolemia in mice to evaluate biochemical and behavioral alterations linked to hypercholesterolemia. Swiss mice were fed a high fat/cholesterol diet (20 % fat and 1.25 % cholesterol) for an 8-week period (from 12 to 18 weeks old) and were tested on the object location, forced swimming and elevated plus-maze tasks. We also investigated hypercholesterolemia-induced changes on acetylcholinesterase (AChE) activity, oxidative damage, amyloid precursor protein (APP) processing and blood brain barrier (BBB) integrity within the prefrontal cortex and hippocampus. It was found that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced short-term memory impairments. We observed no signs of antioxidant imbalance and/or oxidative damage or changes in cortical and hippocampal densities of beta-site amyloid precursor protein-cleaving enzyme 1 and aquaporin-4, biomarkers of APP processing and BBB integrity, respectively. In addition, we treated SH-SY5Y human neuroblastoma cells with low-density lipoprotein (LDL) cholesterol in an attempt to manipulate cell cholesterol content. Notably, LDL cholesterol increased in a dose-dependent manner the activity of AChE in SH-SY5Y cells. The present findings provide new evidence that increased AChE activity within the prefrontal cortex and hippocampus is an early event associated with hypercholesterolemia-induced cognitive impairments.
authors.affiliation: Departamento de Farmacologia, Universidade Federal de Santa Catarina, Florianópolis, SC, 88040-900, Brazil, eduardoluiz26@gmail.com.
authors.forename: Eduardo Luiz Gasnhar
authors.initials: EL
authors.lastname: Moreira
authors.forename: Jade
authors.initials: J
authors.lastname: de Oliveira
authors.forename: Daiane Fátima
authors.initials: DF
authors.lastname: Engel
authors.forename: Roger
authors.initials: R
authors.lastname: Walz
authors.forename: Andreza Fabro
authors.initials: AF
authors.lastname: de Bem
authors.forename: Marcelo
authors.initials: M
authors.lastname: Farina
authors.forename: Rui Daniel S
authors.initials: RD
authors.lastname: Prediger
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology; D006937:Hypercholesterolemia / Q000150:complications*; D008055:Lipids / Q000097:blood; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000209:etiology* / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000473:pathology; D017397:Prefrontal Cortex / Q000201:enzymology; D013550:Swimming / Q000523:psychology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology*
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D001786:Blood Glucose; D008055:Lipids; D017392:Thiobarbituric Acid Reactive Substances; D005980:Glutathione Reductase; D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D005978:Glutathione