Alterations of neurovascular insulin receptor in Alzheimer's disease.

Abstract

The hypothesis that central insulin resistance plays a role in Alzheimer's disease (AD) is gaining interest. However, insulin is secreted by the pancreas and must first interact with the blood-brain barrier (BBB) before having an impact on brain function. In addition, β-amyloid peptides (Aβ) can compete with insulin binding to its insulin receptor (INSR). The aim of the present study was thus to investigate the association between INSR and Aβ in brain microvessels isolated from frozen human brain samples. We used microvessel-enriched brain samples from the Religious Order Study from individuals classified as either Controls, mild cognitive impaired (MCI), or AD. First, the INSR was found enriched in human brain microvessels, compared to parenchymal samples. We next observed lower levels of the INSR precursor (proINSR) and INSRα-B in the parietal cortex of subject diagnosed with AD, while INSRβ remained unchanged between groups. A shift toward a higher INSRα-A: INSRα-B ratio was present in AD brain, consistent with insulin resistance. Western blot analyses showed that INSRα-B levels positively correlated with cognitive scores. Moreover, proINSR, and mature INSR (INSRβ and INSRα-B) were inversely correlated with Aβ plaques in brain cortex and β-site APP cleaving enzyme 1 (BACE1) of microvessels. In addition, positive associations between Insulin-degrading enzyme (IDE) and neprilysin or ATP Binding Cassette Subfamily B Member 1 (ABCB1) were established. Overall, our data support the hypothesis of brain insulin resistance in AD, implicating INSR localized in microvessels. Alterations of vascular INSR were associated with ante mortem cognitive impairment and with Aβ or proteins involved in its production or clearance.