Interactions between insulin, the blood‐brain barrier, and beta‐amyloid in Alzheimer's disease

Abstract

Background Defects in central response to insulin is suspected to play a role in AD. However, to act on the brain, pancreas‐secreted insulin must interact first with the blood‐brain barrier (BBB). The aim of the present study was to better understand mechanisms underlying transport and cell‐signaling of insulin at the BBB, and how they are altered in AD. Method We used microvessel‐enriched brain samples from individual classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages, exposed or not to a high fat diet. In situ cerebral perfusion was used to quantify the transport of [125I] insulin across the BBB. Results We first show that insulin receptors (INSR) in human and mouse brains are concentrated in blood microvessels. We observed lower concentrations of INSRα in microvessel extracts from the parietal cortex of AD patients, associated with cognitive symptoms. We also observed a shift toward a higher INSRα‐A: INSRα‐B ratio in AD, which is consistent with insulin resistance. We next looked at insulin‐activated cell‐signaling pathways within microvessels and found that activation was reduced in 3xTg‐AD mice, following a high‐fat diet. Although it is assumed that insulin crosses the BBB, we found that its transport rate remained very low and was not antagonized by INSR blockers. Finally, we provide some insights on the regulation of brain beta‐amyloid levels following the activation of BBB INSR. Conclusion Overall, our data support the hypothesis of brain insulin resistance in AD, but at the level of INSR localized in microvessels. This also suggests that the INSR and its downstream signaling within endothelial cells of the BBB may be a systemically accessible drug target in AD.