Alzheimer-like changes in rat models of spontaneous diabetes

Abstract

OBJECTIVE - To examine whether changes characteristic of Alzheimer's disease occur in two rat models with spontaneous onset of type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS - The frontal cortices of 8-month-diabetic rats were examined with respect to neuronal densities, neurite degeneration, expression, and/or immunolocalization of amyloid precursor protein (APP), β-secretase, β-amyloid, COOH-terminal fragment (CTF), insulin receptor, IGF-1 receptor, glycogen synthase kinase 3-β (GSK-3β), protein kinase B (Akt), phosphorylated τ (phospho-τ), synaptophysin, and phosphorylated neurofilaments (SMI-31). RESULTS - Neuronal loss occurred in both models, significantly more so in type 2 diabetic BBZDR/Wor rats compared with type 1 diabetic BB/Wor rats and was associated with a ninefold increase of dystrophic neurites. APP, β-secretase, β-amyloid, and CTF were significantly increased in type 2 diabetic rats, as was phospho-τ. The insulin receptor expression was decreased in type 1 diabetes, whereas IGF-1 receptor was decreased in both models, as were Akt and GSK-3β expression. CONCLUSIONS - The data show that β-amyloid and phospho-τ accumulation occur in experimental diabetes and that this is associated with neurite degeneration and neuronal loss. The changes were more severe in the type 2 diabetic model and appear to be associated with insulin resistance and possibly hypercholesterolemia. The two models will provide useful tools to unravel further mechanistic associations between diabetes and Alzheimer's disease. © 2007 by the American Diabetes Association.