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

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 Panzenboeck

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20 Scopus citations

Abstract

Aberrant 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 vitro studies using primary porcine (p)BCEC revealed that Aβ peptides 1–40 or 1–42 (240 nM) reduced cellular levels and interaction of LRP-1 and IR-β thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that Aβ treatment accelerated the autophagy-lysosomal degradation of IR-β and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-β levels through post-translational pathways further deteriorating insulin-mediated responses at the BBB. Our findings indicate that LRP-1 proves important for insulin signaling at the BBB. Cerebral Aβ burden in AD may accelerate LRP-1 and IR-β degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.

Original languageEnglish (US)
Article number103390
JournalMolecular and Cellular Neuroscience
Volume99
DOIs
StatePublished - Sep 2019

Bibliographical note

Funding Information:
This work was supported by the Austrian Science Fund FWF ( DK-MCD W1226 (U.P., D.K.), P24783 (U.P.), and I3535 (A.L.), and the PhD program “Molecular Medicine” of the Medical University of Graz. We further thank BioTechMed-Graz (Flagship Project “Lipases and Lipid Signaling” to A.L. and D.K.).

Publisher Copyright:
© 2019 The Authors

Keywords

  • Alzheimer's disease
  • Amyloid-β peptides
  • Autophagy-lysosomal pathway
  • Blood-brain barrier
  • Endothelial cells
  • Insulin receptor-beta
  • Insulin signaling
  • Low-density lipoprotein receptor-related protein-1

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