ACUTE AMYLOID-Β 40 EXPOSURE DISRUPTS METABOLIC INSULIN SIGNALING IN BLOOD-BRAIN BARRIER ENDOTHELIAL CELLS
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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—the principal 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 empirical-Bayes-stabilized linear models with FDR correction.
Results
Aβ40 reduced insulin-stimulated Akt phosphorylation and converted insulin’s normal inhibition of AMPK into modest stimulation, increasing AMPKα Thr172 and ACC Ser79 phosphorylation. Aβ42 did not alter insulin-stimulated Akt signaling, indicating isoform-specific disruption of endothelial insulin responses. Without insulin, both Aβ40 and Aβ42 showed modest stimulation of ribosomal protein s6.
Conclusions
These findings show that Aβ40 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.
