Amyloid-β neurotoxicity restricts glucose window for neuronal survival in rat hippocampal slice cultures

Diabetes may increase the risk of Alzheimer s disease (AD) However a preventive strategy to combat cognitive decline in diabetic elderly with preexisting AD has remained unknown The aim of this study was to determine the effects of metabolic perturbation on amyloid-beta (A beta) neurotoxicity and the optimal glucose range for improved neuronal survival which is referred to as the glucose window Organotypic hippocampal slice cultures were incubated in either normoglycemic or hyperglycemic medium for 48 h and subsequently treated in experimental media containing 0-30 mM glucose with and without A beta(25-35) Neuronal survival was evaluated by the propidium iodide method A beta neurotoxicity was exacerbated during hypoglycemia/hyperglycemia (<= 2 mM/>= 30 mM) without A beta and <= 3 mM/>= 20 mM with A beta ROS elevated in the respective glucose ranges and supplementation of ROS scavengers effectively improved neuronal survival Interestingly a sharp and sudden drop in glucose levels from preceding hyperglycemia further increased A beta neurotoxicity Supplementation of pyruvate protected exacerbated A beta neurotoxicity These results indicate that increased oxidative stress during severe hypoglycemia hyperglycemia and fluctuation of blood glucose enhances neuronal cell death resulting in the extremely limited glucose window and therefore suggest that careful management of glucose avoiding hypoglycemia is needed to prevent brain degeneration in diabetic patients with AD (C) 2010 Elsevier Inc All rights reserved