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

• Published in: Molecular and cellular neuroscience Vol. 99; p. 103390
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2019
• Subjects: Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Peptides - pharmacology; Amyloid-β peptides; Animals; Autophagy; Autophagy-lysosomal pathway; Blood-brain barrier; Blood-Brain Barrier - cytology; Blood-Brain Barrier - metabolism; Cells, Cultured; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Female; Humans; Insulin - metabolism; Insulin receptor-beta; Insulin signaling; Low Density Lipoprotein Receptor-Related Protein-1 - metabolism; Low-density lipoprotein receptor-related protein-1; Lysosomes - metabolism; Male; Mice; Mice, Inbred C57BL; Receptor, Insulin - metabolism; Signal Transduction; Swine; BCEC; APP; BBB; HFIP; HPRT-1; LC3B; HFD; sLRP-1; PFA; Aβ; BSA; PI3-K; mBCEC; LAMP-1; PSMD4; Blood-brain barrier; NEFA; IB; IF; Alzheimer's disease; Autophagy-lysosomal pathway; mm; ATG3; BCA; CAA; AD; IR-β; MAPK; Amyloid-β peptides; PVDF; PECAM/CD31; HSP27; FA; NTC; APN/CD13; Insulin receptor-beta; PDGFR-β; RT; IRS-1; pBCEC; BM; HCl; SF; CSF; ATG5; IR(s); NTg; ss; DEA; KO; Endothelial cells; 3XTg-AD; LRP-1; OGTT; Low-density lipoprotein receptor-related protein-1; Insulin signaling
• ISSN: 1044-7431; 1095-9327; 1095-9327
• DOI: 10.1016/j.mcn.2019.103390

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. [Display omitted] •LRP-1/IR-β homeostasis is impaired in brain and BBB of male and female 3XTg-AD mice.•HFD feeding reduced cerebral and hepatic but not cerebrovascular LRP-1 levels.•Low IR-β/LRP-1 levels correlate with amyloid burden and cerebral/cerebrovascular autophagy.•Aβ accelerates autophagy-lysosomal degradation of IR-β/LRP-1 in pBCEC.•LRP-1 regulates IR-β expression by modulating its post-translational modification in pBCEC.