Acute amyloid-β exposure disrupts insulin signaling in blood-brain barrier endothelial cell culture models.

Background: Brain insulin resistance and cerebrovascular dysfunction emerge early in late-onset Alzheimer's disease, but how amyloid-β (Aβ) disrupts insulin signaling at the cerebrovascular blood-brain barrier-a major site of insulin receptor signaling and transport into the brain-remains unclear. Methods: We exposed two distinct human blood-brain-barrier endothelial cell models to soluble Aβ40 or Aβ42 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 linear models. Results: Aβ40 reduced insulin-stimulated Akt activation and converted insulin's normal inhibition of AMPK into modest stimulation. Aβ42 did not alter insulin-stimulated Akt signaling but moderately suppressed basal Akt activation. Conclusions: These findings suggest that Aβ40 acutely impairs insulin signal transduction in BBB endothelial cells, supporting a model in which vascular Aβ exposure contributes directly to the early development of brain insulin resistance in AD.