학술논문
A beta efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas
Document Type
Author
Verma, N.; Velmurugan, G. V.; Winford, E.; Coburn, H.; Kotiya, D.; Leibold, N.; Radulescu, L.; Despa, S.; Chen, K. C.; Van Eldik, L. J.; Nelson, P. T.; Wilcock, D. M.; Jicha, G. A.; Stowe, A. M.; Goldstein, L. B.; Powel, D. K.; Walton, J. H.; Navedo, M. F.; Nystoriak, M. A.; Murray, A. J.; Biessels, G. J.; Troakes, C.; Zetterberg, Henrik, 1973; Hardy, J.; Lashley, T.; Despa, F.
Source
Communications Biology. 6(1)
Subject
Language
English
Abstract
Impairment of vascular pathways of cerebral beta-amyloid (A beta) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral A beta clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with A beta within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-A beta co-deposits. LRP1-mediated A beta transport across the blood-brain barrier and A beta clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by A beta deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and A beta pathology.