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-β (Aβ) 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 Aβ(25-35). Neuronal survival was evaluated by the propidium iodide method. Aβ neurotoxicity was exacerbated during hypoglycemia/hyperglycemia (≦2 mM/≧30 mM) without Aβ and ≦3 mM/≧20 mM with Aβ. 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 Aβ neurotoxicity. Supplementation of pyruvate protected exacerbated Aβ 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.
Wang
Xiaonan
X
Department of Internal and Geriatric Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
Song
Xiuzhen
X
Takata
Toshihiro
T
Miichi
Yoshiaki
Y
Yokono
Koichi
K
Sakurai
Takashi
T
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D006943:Hyperglycemia / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism; D066298:In Vitro Techniques; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D018384:Oxidative Stress; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D001786:Blood Glucose; D009498:Neurotoxins