Brain microvascular injury and white matter disease provoked by
diabetes-associated hyperamylinemia.
Authors Ly H, Verma N, Wu F, Liu M, Saatman KE, Nelson PT, Slevin JT, Goldstein LB,
Biessels GJ, Despa F
Submitted By Florin Despa on 7/25/2017
Status Published
Journal Annals of neurology
Year 2017
Date Published 7/1/2017
Volume : Pages Not Specified : Not Specified
PubMed Reference 28696548
Abstract The brain blood vessels of patients with type-2 diabetes and dementia have
deposition of amylin, an amyloidogenic hormone co-secreted 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 the
amylin transport in the brain via plasma apolipoproteins., 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.,
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.,
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. This
article is protected by copyright. All rights reserved.

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