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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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 1 2019

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Lipoprotein Receptors
Insulin Receptor
Autophagy
Blood-Brain Barrier
Amyloid
Alzheimer Disease
Endothelial Cells
Insulin
Proteins
Brain
In Vitro Techniques
Low Density Lipoprotein Receptor-Related Protein-1
High Fat Diet
Swine

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

PubMed: MeSH publication types

  • Journal Article

Cite this

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. / Gali, Chaitanya Chakravarthi; Fanaee-Danesh, Elham; Zandl-Lang, Martina; Albrecher, Nicole Maria; Tam-Amersdorfer, Carmen; Stracke, Anika; Sachdev, Vinay; Reichmann, Florian; Sun, Yidan; Avdili, Afrim; Reiter, Marielies; Kratky, Dagmar; Holzer, Peter; Lass, Achim; Kandimalla, Karunya K; Panzenboeck, Ute.

In: Molecular and Cellular Neuroscience, Vol. 99, 103390, 01.09.2019.

Research output: Contribution to journalArticle

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 2019, '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', Molecular and Cellular Neuroscience, vol. 99, 103390. https://doi.org/10.1016/j.mcn.2019.103390
Gali, Chaitanya Chakravarthi ; Fanaee-Danesh, Elham ; Zandl-Lang, Martina ; Albrecher, Nicole Maria ; Tam-Amersdorfer, Carmen ; Stracke, Anika ; Sachdev, Vinay ; Reichmann, Florian ; Sun, Yidan ; Avdili, Afrim ; Reiter, Marielies ; Kratky, Dagmar ; Holzer, Peter ; Lass, Achim ; Kandimalla, Karunya K ; Panzenboeck, Ute. / 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. In: Molecular and Cellular Neuroscience. 2019 ; Vol. 99.
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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 (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.",
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AU - Gali, Chaitanya Chakravarthi

AU - Fanaee-Danesh, Elham

AU - Zandl-Lang, Martina

AU - Albrecher, Nicole Maria

AU - Tam-Amersdorfer, Carmen

AU - Stracke, Anika

AU - Sachdev, Vinay

AU - Reichmann, Florian

AU - Sun, Yidan

AU - Avdili, Afrim

AU - Reiter, Marielies

AU - Kratky, Dagmar

AU - Holzer, Peter

AU - Lass, Achim

AU - Kandimalla, Karunya K

AU - Panzenboeck, Ute

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Amyloid-β peptides

KW - Autophagy-lysosomal pathway

KW - Blood-brain barrier

KW - Endothelial cells

KW - Insulin receptor-beta

KW - Insulin signaling

KW - Low-density lipoprotein receptor-related protein-1

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