Amylin-mediated regulation of LRP1 by miR-103/107 impairs β-amyloid efflux

BACKGROUND: To determine whether systemic pancreatic amylin dyshomeostasis impairs the efflux of amyloid-β (Aβ) across the blood-brain barrier (BBB), we studied cerebral microvessels in humans and a rat model of pancreatic amylin dyshomeostasis, and evaluated the effect of human amylin in an in vitro BBB model. METHOD: Brain sections from Alzheimer's Disease (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 RESULT: In human AD brains, Aβ accumulation within the perivascular space frequently co-localizes 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 promote amylin deposition in brain capillaries, increase brain Aβ level, lower plasma-to-brain Aβ ratio and suppress 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. CONCLUSION: High blood human amylin levels cause cerebral microvascular dysfunction and interferes with Aβ efflux across the BBB through miRNA-mediated LRP1 downregulation. Lowering blood amylin level in early AD could improve Aβ clearance from the brain.

Duke Scholars

Author Larry Bruce Goldstein Neurology, Stroke and Vascular Neurology