OBJECTIVE: The brain blood vessels of patients with type 2 diabetes and dementia have deposition of amylin, an amyloidogenic hormone cosecreted with insulin. It is not known whether vascular amylin deposition is a consequence or a trigger of vascular injury. We tested the hypothesis that the vascular amylin deposits cause endothelial dysfunction and microvascular injury and are modulated by amylin transport in the brain via plasma apolipoproteins.
METHODS: Rats overexpressing amyloidogenic (human) amylin in the pancreas (HIP rats) and amylin knockout (AKO) rats intravenously infused with aggregated amylin were used for in vivo phenotyping. We also carried out biochemical analyses of human brain tissues and studied the effects of the aggregated amylin on endothelial cells ex vivo.
RESULTS: Amylin deposition in brain blood vessels is associated with vessel wall disruption and abnormal surrounding neuropil in patients with type 2 diabetes and dementia, in HIP rats, and in AKO rats infused with aggregated amylin. HIP rats have brain microhemorrhages, white matter injury, and neurologic deficits. Vascular amylin deposition provokes loss of endothelial cell coverage and tight junctions. Intravenous infusion in AKO rats of human amylin, or combined human amylin and apolipoprotein E4, showed that amylin binds to plasma apolipoproteins. The intravenous infusion of apolipoprotein E4 exacerbated the brain accumulation of aggregated amylin and vascular pathology in HIP rats.
INTERPRETATION: These data identify vascular amylin deposition as a trigger of brain endothelial dysfunction that is modulated by plasma apolipoproteins and represents a potential therapeutic target in diabetes-associated dementia and stroke. Ann Neurol 2017;82:208-222.
Digital Object Identifier (DOI)
This research was supported by National Institutes of Health (R01AG053999, R01HL118474 and pilot fund from Sanders-Brown Center on Aging AG028383-09 to FD), Alzheimer’s Association (VMF-15-363458 to FD) and American Stroke Association (16GRNT310200 to FD).
Ly, Han; Verma, Nirmal; Wu, Fengen; Liu, Miao; Saatman, Kathryn E.; Nelson, Peter T.; Slevin, John T.; Goldstein, Larry B.; Biessels, Geert Jan; and Despa, Florin, "Brain Microvascular Injury and White Matter Disease Provoked by Diabetes-Associated Hyperamylinemia" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 103.
Supporting Information Table
NIHMS891898-supplement-Supp_VideoS1Female.mp4 (35402 kB)
Supporting Information Video 1. Video record comparing the behavior in a female human amylin‐expressing rat (the HIP rat) vs. wild type rats at 18 months of age.
NIHMS891898-supplement-Supp_VideoS2Male.mp4 (43902 kB)
Supporting Information Video 2. Video record comparing the behavior in a male human amylin‐expressing rat (the HIP rat) vs. a wild type (WT) littermate rat (15 months of age).