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Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.

Publication ,  Journal Article
Ly, H; Verma, N; Wu, F; Liu, M; Saatman, KE; Nelson, PT; Slevin, JT; Goldstein, LB; Biessels, GJ; Despa, F
Published in: Ann Neurol
August 2017

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.

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Published In

Ann Neurol

DOI

EISSN

1531-8249

Publication Date

August 2017

Volume

82

Issue

2

Start / End Page

208 / 222

Location

United States

Related Subject Headings

  • Tight Junctions
  • Rats, Mutant Strains
  • Rats
  • Pancreas
  • Neurology & Neurosurgery
  • Neuroimaging
  • Motor Skills
  • Microvessels
  • Maze Learning
  • Magnetic Resonance Imaging
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ly, H., Verma, N., Wu, F., Liu, M., Saatman, K. E., Nelson, P. T., … Despa, F. (2017). Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol, 82(2), 208–222. https://doi.org/10.1002/ana.24992
Ly, Han, Nirmal Verma, Fengen Wu, Miao Liu, Kathryn E. Saatman, Peter T. Nelson, John T. Slevin, Larry B. Goldstein, Geert Jan Biessels, and Florin Despa. “Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.Ann Neurol 82, no. 2 (August 2017): 208–22. https://doi.org/10.1002/ana.24992.
Ly H, Verma N, Wu F, Liu M, Saatman KE, Nelson PT, et al. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol. 2017 Aug;82(2):208–22.
Ly, Han, et al. “Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia.Ann Neurol, vol. 82, no. 2, Aug. 2017, pp. 208–22. Pubmed, doi:10.1002/ana.24992.
Ly H, Verma N, Wu F, Liu M, Saatman KE, Nelson PT, Slevin JT, Goldstein LB, Biessels GJ, Despa F. Brain microvascular injury and white matter disease provoked by diabetes-associated hyperamylinemia. Ann Neurol. 2017 Aug;82(2):208–222.
Journal cover image

Published In

Ann Neurol

DOI

EISSN

1531-8249

Publication Date

August 2017

Volume

82

Issue

2

Start / End Page

208 / 222

Location

United States

Related Subject Headings

  • Tight Junctions
  • Rats, Mutant Strains
  • Rats
  • Pancreas
  • Neurology & Neurosurgery
  • Neuroimaging
  • Motor Skills
  • Microvessels
  • Maze Learning
  • Magnetic Resonance Imaging