The role of the blood‐brain barrier in brain insulin signaling

Abstract

AbstractBackgroundDefects 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 insulin receptor (INSR) consists in 2 insulin‐binding extracellular α chains, either short (INSRα‐A) or long (INSRα‐B) isoforms, as well as 2 intracellular β‐chains (INSRβ) containing auto‐phosphorylation sites. The aim of the present study was to better understand the role of INSR located on the BBB in AD.MethodWe used microvessel‐enriched brain samples from individuals classified as Controls, MCI or AD and from 3xTg‐AD mice from different ages. In situ cerebral perfusion was used to directly assess the interaction between circulating insulin and the BBB.ResultsWe first show that INSR in human and mouse brains are concentrated in blood microvessels, with INSRα‐B being almost absent from the parenchymal fractions. Lower levels of INSRα‐B were observed in microvessel extracts from the parietal cortex of AD persons, associated with cognitive decline. The resulting shift toward a higher INSRα‐A:INSRα‐B ratio is consistent with insulin resistance situated on the BBB. Intracarotid infusion of insulin induced a rapid phosphorylation of INSRβ retrieved from cerebrovascular extracts, but not from parenchymal extracts of the mouse brain. In the 3xTg‐AD mouse model of AD neuropathology, lower levels of cerebrovascular INSRα‐B were observed whereas activation of INSRβ was blunted upon intracarotid administration of insulin. Finally, we provide some insights on a possible association between BACE1 activation and the reduction of cerebrovascular INSR.ConclusionOverall, data gathered from postmortem AD brains and an animal model of AD neuropathology suggest that brain insulin resistance in AD may occur at the level of INSR located on microvessels. These results also indicate that INSR and its downstream signaling within endothelial cells of the BBB are systemically accessible drug targets in AD.