Amyloid-beta impairs insulin signaling by accelerating autophagy-lysosomal degradation of LRP-1 and IR-β in blood-brain barrier endothelial cells in vitro and in 3XTg-AD mice

Publication date: Available online 2 July 2019Source: Molecular and Cellular NeuroscienceAuthor(s): Chaitanya Chakravarthi Gali, Elham Fanaee-Danesh, Martina Zandl-Lang, Nicole Maria Albrecher, Carmen Tam-Amersdorfer, Anika Stracke, Vinay Sachdev, Florian Reichmann, Yidan Sun, Afrim Avdili, Marielies Reiter, Dagmar Kratky, Peter Holzer, Achim Lass, Karunya K. Kandimalla, Ute PanzenboeckAbstractAberrant insulin signaling constitutes an early change in Alzheimer's disease (AD). Insulin receptors (IR) and low-density lipoprotein receptor-related protein-1 (LRP-1) are expressed in brain capillary endothelial cells (BCEC) forming the blood-brain barrier (BBB). There, insulin may regulate the function of LRP-1 in Aβ clearance from the brain. Changes in IR-β and LRP-1 and insulin signaling at the BBB in AD are not well understood. Herein, we identified a reduction in cerebral and cerebrovascular IR-β levels in 9-month-old male and female 3XTg-AD (PS1M146V, APPSwe, and tauP301L) as compared to NTg mice, which is important in insulin mediated signaling responses. Reduced cerebral IR-β levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-β and LRP-1 levels in 3XTg-AD mice correlated with elevated levels of autophagy marker LC3B. In both genotypes, high-fat diet (HFD) feeding decreased cerebral and hepatic LRP-1 expression and elevated cerebral Aβ burden without affecting cerebrovascular LRP-1 and IR-β levels. In vit...
Source: Molecular and Cellular Neuroscience - Category: Neuroscience Source Type: research