Wistar audiogenic rat (WAR): a possible model for the study of Alzheimer's Disease related to insulin resistance

Abstract

Dementia is a highly prevalent neurological disorder, affecting over 46 million people worldwide. Among the known causes, Alzheimer's Disease (AD) is the most predominant one. The main anatomopathological findings in AD are senile plaques, consisting of amyloid beta-protein (A²) accumulation, and neurofibrillary tangles, formed by aggregation of hyperphosphorylated tau protein. It has been hypothesized that AD might be the third type of diabetes. Insulin resistance may be one of the main mechanisms that contribute to this hypothesis. Studies executed in our laboratory demonstrated that the Wistar Audiogenic Rat (WAR) presents a higher amount of A² and phosphorylated tau in its brain, when compared to the control Wistar. Therefore, the aim of the current study is to analyze if the premature increase of A² and phosphorylated tau found in WAR are due to AD and alterations in insulin signaling pathways. To this end, we are going to select 64 90-day-old male wild rats (32 Wistars and 32 WARs) and inject vehicle (2% DMSO in PBS) or amyloid beta oligomers (A²Os) into the right lateral ventricle of their brains. The animals will be tested in the Morris water maze to evaluate their spatial memory performance 48 hours after inoculation of vehicle or A²Os. Then, the rats will be euthanized and their hippocampi will be dissected for Western Blot analysis in order to measure the levels of A², phosphorylated tau, insulin, insulin receptor and phosphorylated insulin receptor substrate 1 (IRS1). Thereby, we propose that the WAR may be a model for the study of AD and present alterations in insulin signaling pathways with effects in the prognosis of this disease. (AU)