Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Gali, CC; Fanaee-Danesh, E; Zandl-Lang, M; Albrecher, NM; Tam-Amersdorfer, C; Stracke, A; Sachdev, V; Reichmann, F; Sun, Y; Avdili, A; Reiter, M; Kratky, D; Holzer, P; Lass, A; Kandimalla, KK; Panzenboeck, U.
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.
Mol Cell Neurosci. 2019; 99: 103390-103390. Doi: 10.1016/j.mcn.2019.103390 [OPEN ACCESS]
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Leading authors Med Uni Graz

Gali Chaitanya Chakravarthi

Panzenboeck Ute

Co-authors Med Uni Graz

Avdili Afrim

Fanaee-Danesh Elham

Holzer Peter

Kratky Dagmar

Reichmann Florian

Sachdev Vinay

Stracke Anika

Sun Yidan

Tam-Amersdorfer Carmen

Zandl-Lang Martina

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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 (PS1_M146V, APP_Swe, and tau_P301L) 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. Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Find related publications in this database (Keywords)

Alzheimer's disease

Amyloid-beta peptides

Low-density lipoprotein receptor-related protein-1

Insulin receptor-beta

Insulin signaling

Blood-brain barrier

Endothelial cells

Autophagy-lysosomal pathway

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