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

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 A? clearance from the brain. Changes in IR-? 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-? 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-? levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-? 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 A? burden without affecting cerebrovascular LRP-1 and IR-? levels. In vitro studies using primary porcine (p)BCEC revealed that A? peptides 1-40 or 1-42 (240?nM) reduced cellular levels and interaction of LRP-1 and IR-? thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that A? treatment accelerated the autophagy-lysosomal degradation of IR-? and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-? 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 A? burden in AD may accelerate LRP-1 and IR-? degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.

SUBMITTER: Gali CC 

PROVIDER: S-EPMC6897558 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature