ACUTE AMYLOID-B 40 EXPOSURE DISRUPTS METABOLIC INSULIN SIGNALING IN BLOOD-BRAIN BARRIER ENDOTHELIAL CELLS

Abstract

BackgroundBrain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimers disease, but how amyloid-{beta} (A{beta}) disrupts insulin signaling at the cerebrovascular blood-brain barrier--the principal site of insulin receptor signaling and transport into the brain--remains unclear. MethodsWe exposed two distinct human blood-brain-barrier endothelial cell models to soluble A{beta}40 or A{beta}42 for 1 h, followed by 100 nM insulin for 10 min. Protein and phosphoprotein responses were quantified by reverse-phase protein array, and differential expression was evaluated using empirical-Bayes-stabilized linear models with FDR correction. ResultsA{beta}40 reduced insulin-stimulated Akt phosphorylation and converted insulins normal inhibition of AMPK into modest stimulation, increasing AMPK Thr172 and ACC Ser79 phosphorylation. A{beta}42 did not alter insulin-stimulated Akt signaling, indicating isoform-specific disruption of endothelial insulin responses. Without insulin, both A{beta}40 and A{beta}42 showed modest stimulation of ribosomal protein s6. ConclusionsThese findings show that A{beta}40 acutely impairs insulin signal transduction in BBB endothelial cells, supporting a model in which vascular amyloid exposure contributes directly to the early development of brain insulin resistance in AD.