Cerebrovascular insulin receptors are defective in Alzheimer's disease

Central response to insulin is suspected to be defective in Alzheimers disease (AD), but its localization in the brain remains unknown. While most insulin is secreted in the bloodstream by the pancreas, how it interacts with the blood-brain barrier (BBB) to alter brain function remains poorly defined. Here, we show that human and murine cerebral insulin receptors (INSR), particularly the long isoform INSR-B, are concentrated in microvessels rather than in the parenchyma. Vascular concentrations of INSR-B were lower in the parietal cortex of subjects diagnosed with AD, positively correlating with cognitive scores, leading to a shift toward a higher INSR-A/B ratio, consistent with cerebrovascular insulin resistance in the AD brain. Vascular INSR was inversely correlated with {beta}-amyloid (A{beta}) plaques and {beta}-site APP cleaving enzyme 1 (BACE1), but positively correlated with insulin-degrading enzyme (IDE), neprilysin and ABCB1. Using brain cerebral intracarotid perfusion, we found that the transport rate of insulin across the BBB remained very low (<0.03 {micro}l.g-1.s-1) and was not inhibited by an INSR antagonist. However, intracarotid perfusion of insulin induced the phosphorylation of INSR{beta} which was restricted to microvessels. Such an activation of vascular INSR was blunted in 3xTg-AD mice, suggesting that AD neuropathology induces insulin resistance at the level of the BBB. Overall, the present data in postmortem AD brains and an animal model of AD indicate that defects in the INSR localized at the BBB strongly contribute to brain insulin resistance in AD, in association with A{beta} pathology. HighlightsO_LICirculating insulin activates brain insulin receptors in microvessels. C_LIO_LIBBB INSR contribute to cerebral insulin resistance in AD. C_LIO_LICognitive impairment in AD is associated with a loss of cerebrovascular INSR-B. C_LIO_LILoss of isoform INSR-B is associated with increased BACE1 activity. C_LI SummaryLeclerc et al. show that circulating insulin activates cerebral insulin receptor localized on the blood-brain-barrier level (BBB), not in the parenchyma. Experiments with human brain samples and animal models provide evidence that INSR at the BBB are impaired in Alzheimers disease, thereby contributing to brain insulin resistance.