Endothelial Adora2a activation promotes blood-brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance

Masaki Yamamoto, De Huang Guo, Caterina M. Hernandez, Alexis Michelle Stranahan

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Obesity and insulin resistance elicit blood- brain barrier (BBB) breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood. These studies initially addressed the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. Obesity increased BBB permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), whereas diet-induced insulin resistance increased permeability to both NaFl and Evans blue, which forms a high molecular weight complex with serum albumin. Serial section transmission electron microscopy analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. Chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and we observed that acute Adora2a antagonism normalized BBB permeability in wild-type mice with diet-induced insulin resistance. Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against BBB breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against BBB breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory. These findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the BBB in dietary obesity, and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance.

Original languageEnglish (US)
Pages (from-to)4179-4192
Number of pages14
JournalJournal of Neuroscience
Volume39
Issue number21
DOIs
StatePublished - May 22 2019
Externally publishedYes

Fingerprint

Blood-Brain Barrier
Insulin Resistance
Diet
Obesity
Endothelial Cells
Permeability
Neuronal Plasticity
Tight Junctions
Molecular Weight
Pericytes
Evans Blue
Purinergic P1 Receptors
Cytoprotection
Fluorescein
Transmission Electron Microscopy
Serum Albumin
Cognition
Blood Vessels
Cognitive Dysfunction
Hippocampus

Keywords

  • Blood-brain barrier
  • Diabetes
  • Hippocampus
  • Neurovascular
  • Obesity

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Endothelial Adora2a activation promotes blood-brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance. / Yamamoto, Masaki; Guo, De Huang; Hernandez, Caterina M.; Stranahan, Alexis Michelle.

In: Journal of Neuroscience, Vol. 39, No. 21, 22.05.2019, p. 4179-4192.

Research output: Contribution to journalArticle

@article{d4d40ce57b57492490cd34e3cd446fd9,
title = "Endothelial Adora2a activation promotes blood-brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance",
abstract = "Obesity and insulin resistance elicit blood- brain barrier (BBB) breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood. These studies initially addressed the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. Obesity increased BBB permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), whereas diet-induced insulin resistance increased permeability to both NaFl and Evans blue, which forms a high molecular weight complex with serum albumin. Serial section transmission electron microscopy analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. Chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and we observed that acute Adora2a antagonism normalized BBB permeability in wild-type mice with diet-induced insulin resistance. Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against BBB breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against BBB breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory. These findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the BBB in dietary obesity, and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance.",
keywords = "Blood-brain barrier, Diabetes, Hippocampus, Neurovascular, Obesity",
author = "Masaki Yamamoto and Guo, {De Huang} and Hernandez, {Caterina M.} and Stranahan, {Alexis Michelle}",
year = "2019",
month = "5",
day = "22",
doi = "10.1523/JNEUROSCI.2506-18.2019",
language = "English (US)",
volume = "39",
pages = "4179--4192",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "21",

}

TY - JOUR

T1 - Endothelial Adora2a activation promotes blood-brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance

AU - Yamamoto, Masaki

AU - Guo, De Huang

AU - Hernandez, Caterina M.

AU - Stranahan, Alexis Michelle

PY - 2019/5/22

Y1 - 2019/5/22

N2 - Obesity and insulin resistance elicit blood- brain barrier (BBB) breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood. These studies initially addressed the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. Obesity increased BBB permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), whereas diet-induced insulin resistance increased permeability to both NaFl and Evans blue, which forms a high molecular weight complex with serum albumin. Serial section transmission electron microscopy analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. Chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and we observed that acute Adora2a antagonism normalized BBB permeability in wild-type mice with diet-induced insulin resistance. Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against BBB breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against BBB breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory. These findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the BBB in dietary obesity, and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance.

AB - Obesity and insulin resistance elicit blood- brain barrier (BBB) breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood. These studies initially addressed the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. Obesity increased BBB permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), whereas diet-induced insulin resistance increased permeability to both NaFl and Evans blue, which forms a high molecular weight complex with serum albumin. Serial section transmission electron microscopy analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. Chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and we observed that acute Adora2a antagonism normalized BBB permeability in wild-type mice with diet-induced insulin resistance. Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against BBB breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against BBB breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory. These findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the BBB in dietary obesity, and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance.

KW - Blood-brain barrier

KW - Diabetes

KW - Hippocampus

KW - Neurovascular

KW - Obesity

UR - http://www.scopus.com/inward/record.url?scp=85066513287&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066513287&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.2506-18.2019

DO - 10.1523/JNEUROSCI.2506-18.2019

M3 - Article

C2 - 30886019

AN - SCOPUS:85066513287

VL - 39

SP - 4179

EP - 4192

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 21

ER -