Journal
MOLECULAR AND CELLULAR NEUROSCIENCE
Volume 99, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.mcn.2019.103390
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
Categories
Funding
- Austrian Science Fund FWF [DK-MCD W1226, P24783, I3535]
- PhD program Molecular Medicine of the Medical University of Graz
- Austrian Science Fund (FWF) [P24783, I3535] Funding Source: Austrian Science Fund (FWF)
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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 beta clearance from the brain. Changes in IR-beta 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-beta 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-beta levels corresponded to impaired insulin signaling and LRP-1 levels in brain. Reduced cerebral and cerebrovascular IR-beta 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 beta burden without affecting cerebrovascular LRP-1 and IR-beta levels. In vitro studies using primary porcine (p)BCEC revealed that A beta peptides 1-40 or 1-42 (240 nM) reduced cellular levels and interaction of LRP-1 and IR-beta thereby perturbing insulin-mediated signaling. Further mechanistic investigation revealed that A beta treatment accelerated the autophagy-lysosomal degradation of IR-beta and LRP-1 in pBCEC. LRP-1 silencing in pBCEC decreased IR-beta 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 beta burden in AD may accelerate LRP-1 and IR-beta degradation in BCEC thereby contributing to impaired cerebral and cerebromicrovascular insulin effects.
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