The pathological interaction between diabetes and presymptomatic Alzheimer's disease.
Since diabetes is a risk factor for Alzheimer's disease (AD), we asked if there is a functional interaction between high glucose and elevated beta amyloid peptide (Abeta) in cultured brain microvascular endothelial cells and presymptomatic AD transgenic mice. When cultured brain microvascular endothelial cells are exposed to both high glucose and low levels of Abeta, there is a synergistic interaction to cause an increased accumulation of advanced glycation products (AGE) and reactive oxygen species (ROS). When presymptomatic mice expressing mutant human amyloid precursor protein and presenilin are made diabetic, they have a decrease in cognitive function relative to control mice. Associated with the cognitive deficit are increases in brain microvascular AGE and iNOS expression, and the loss of the synaptic spine protein drebrin. No amyloid plaques or tangles are observed within the brains of any group. These data show that diabetes causes a synergistic potentiation of some indices of AD in transgenic animals that are presymptomatic for the classical features of the disease.
Burdo
Joseph R
JR
Cellular Neurobiology Laboratory, The Salk Institute For Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037-1099, USA. burdo@salk.edu
Chen
Qi
Q
Calcutt
Nigel A
NA
Schubert
David
D
D000544:Alzheimer Disease / Q000235:genetics / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000503:physiopathology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology; D008297:Male; D008569:Memory Disorders / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D055806:Microvessels / Q000502:physiology; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D053763:Presenilins / Q000235:genetics; D058255:Protease Nexins; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics
D016564:Amyloid beta-Protein Precursor; D017127:Glycation End Products, Advanced; D009479:Neuropeptides; D053763:Presenilins; D058255:Protease Nexins; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; C053386:drebrins; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse