Wistar Audiogenic Rat (WAR): a possible model for the study of Alzheimer\'s disease related to insulin resistance

The Wistar Audiogenic Rat (WAR), a genetic model of epilepsy, presents many comorbidities. Previous data suggested elevated brain levels of phosphorylated tau (pTau), one of the the main hallmarks of Alzheimer\'s Disease (AD). Recent studies have hypothesized AD as the third type of diabetes. Therefore, the aim of this study was to validate the WAR strain as a model to study AD and correlate with alterations in the insulin signaling pathway regulation. To this end, we selected 63 male adult and aged animals (n=28 Wistars, 14 Wistars Hannover and 21 WARs). The animals were subjected to the Morris Water Maze (MWM) test. After the MWM, the rats were euthanized and their ventral (VH) and dorsal (DH) hippocampi were dissected for Western blot analysis in order to measure the expression levels of A?, tau, pTau (S396), insulin receptor (IR), alpha and beta phosphorylated glycogen synthase kinase 3 (pGSK-3?/? Ser21/9), and phospho-insulin receptor substrate-1 (pIRS-1 S312) in the ventral (VH) and dorsal hippocampus (DH) by means of the Western blotting method. The results were confirmed by immunohistochemical analysis. Both adult and aged WARs showed longer latency to find the escape platform during the learning period and most retests of the MWM. The adult WARs presented lower A? and IR expression in the VH, higher pGSK-3?/? (S21/9) expression in the DH, and higher levels of positive cells for pIRS-1 (S312) in the hippocampus. The aged WARs presented higher pTau (S396) expression in both VH and DH, lower A? and IR expression in the VH, higher pGSK-3?/? (S21/9) expression in both VH and DH. Although the WAR animals were primarily selected to study epilepsy, our findings in this study suggest the coexistence of an AD-like phenotype and central insulin resistance in addition to the initially selected epilepsy phenotype. Therefore, other molecular and histological studies are needed to better understand our data and to validate the WAR strain as a model to study the relationship between AD and central insulin resistance. (AU)