Amylin-mediated regulation of LRP1 by miR-103/107 induces cerebral microvascular dysfunction and impairs β-amyloid efflux

Abstract Background: The cerebral small blood vessels of individuals with Alzheimer’s Disease (AD) often have deposits of amylin, an amyloid-forming protein secreted in the blood by pancreatic β-cells. To determine whether systemic pancreatic amylin dyshomeostasis impairs amyloid β (Aβ) efflux across the blood-brain barrier (BBB), we studied cerebral microvessels in humans and rats with pancreatic expression of amyloidogenic human amylin, and evaluated the effect of human amylin in an in vitro BBB model. Methods: Brain sections from AD and cognitively unimpaired individuals were co-stained with anti-Aβ and anti-amylin antibodies. In vivo analyses of Aβ efflux across the BBB were carried out in aged rats that express amyloid-forming human amylin in pancreatic β-cells and littermates expressing non-amyloidogenic rat amylin. We also used an in vitro BBB model of Aβ transcytosis in which the endothelial cell monolayer was exposed to amylin-mediated stress to determine whether amylin stress downregulates LRP1, the Aβ efflux transporter. This allowed us to use pharmacology to rescue the endothelial LRP1. Results: In human AD brains, Aβ accumulation within the perivascular space frequently co-localized with deposits of amylin in the vessel wall. In rats with pancreatic expression of amyloid-forming human amylin, the high blood levels of human amylin promoted amylin deposition in brain capillaries, increased brain Aβ level, lowered plasma-to-brain Aβ ratio and suppressed expression of LRP1 protein. In vitro BBB model experiment revealed that amylin-induced stress downregulates LRP1 in endothelial cells through a miRNA-based translational repression mechanism. Conclusions: High blood human amylin levels cause cerebral microvascular dysfunction and interfere with Aβ efflux across the BBB through miRNA-mediated LRP1 downregulation. Lowering the blood amylin level in early AD could improve Aβ clearance from the brain.