TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits

Trevor Hardigan, Caterina M. Hernandez, Rebecca Ward, M. Nasrul Hoda, Adviye Ergul

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetesinduced impairment of long-term hippocampal and prefrontal cortexmediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.

Original languageEnglish (US)
Pages (from-to)R927-R937
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume312
Issue number6
DOIs
StatePublished - Jun 1 2017

Fingerprint

Cerebrovascular Circulation
Diabetic Angiopathies
Perfusion
Toll-Like Receptors
Anti-Anxiety Agents
Vascular Endothelium
Diabetes Complications
Type 1 Diabetes Mellitus
Chemokines
Fear
Blood Vessels
Dementia
Immune System
Learning
Cytokines
Phenotype
Cognitive Dysfunction

Keywords

  • Cerebral perfusion
  • Cerebrovascular
  • Cognitive impairment
  • Diabetes
  • Toll-like receptor 2

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits. / Hardigan, Trevor; Hernandez, Caterina M.; Ward, Rebecca; Nasrul Hoda, M.; Ergul, Adviye.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 312, No. 6, 01.06.2017, p. R927-R937.

Research output: Contribution to journalArticle

Hardigan, Trevor ; Hernandez, Caterina M. ; Ward, Rebecca ; Nasrul Hoda, M. ; Ergul, Adviye. / TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2017 ; Vol. 312, No. 6. pp. R927-R937.
@article{ae7d4332f3cf4dba8656006968620572,
title = "TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits",
abstract = "The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetesinduced impairment of long-term hippocampal and prefrontal cortexmediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.",
keywords = "Cerebral perfusion, Cerebrovascular, Cognitive impairment, Diabetes, Toll-like receptor 2",
author = "Trevor Hardigan and Hernandez, {Caterina M.} and Rebecca Ward and {Nasrul Hoda}, M. and Adviye Ergul",
year = "2017",
month = "6",
day = "1",
doi = "10.1152/ajpregu.00482.2016",
language = "English (US)",
volume = "312",
pages = "R927--R937",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "6",

}

TY - JOUR

T1 - TLR2 knockout protects against diabetes-mediated changes in cerebral perfusion and cognitive deficits

AU - Hardigan, Trevor

AU - Hernandez, Caterina M.

AU - Ward, Rebecca

AU - Nasrul Hoda, M.

AU - Ergul, Adviye

PY - 2017/6/1

Y1 - 2017/6/1

N2 - The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetesinduced impairment of long-term hippocampal and prefrontal cortexmediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.

AB - The risk of cognitive decline in diabetes (Type 1 and Type 2) is significantly greater compared with normoglycemic patients, and the risk of developing dementia in diabetic patients is doubled. The etiology for this is likely multifactorial, but one mechanism that has gained increasing attention is decreased cerebral perfusion as a result of cerebrovascular dysfunction. The innate immune system has been shown to play a role in diabetic vascular complications, notably through the Toll-like receptor (TLR)-stimulated release of proinflammatory cytokines and chemokines that lead to vascular damage. TLR2 has been implicated in playing a crucial role in the development of diabetic microvascular complications, such as nephropathy, and thus, we hypothesized that TLR2-mediated cerebrovascular dysfunction leads to decreased cerebral blood flow (CBF) and cognitive impairment in diabetes. Knockout of TLR2 conferred protection from impaired CBF in early-stage diabetes and from hyperperfusion in long-term diabetes, prevented the development of endothelium-dependent vascular dysfunction in diabetes, created a hyperactive and anxiolytic phenotype, and protected against diabetesinduced impairment of long-term hippocampal and prefrontal cortexmediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.

KW - Cerebral perfusion

KW - Cerebrovascular

KW - Cognitive impairment

KW - Diabetes

KW - Toll-like receptor 2

UR - http://www.scopus.com/inward/record.url?scp=85020202209&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020202209&partnerID=8YFLogxK

U2 - 10.1152/ajpregu.00482.2016

DO - 10.1152/ajpregu.00482.2016

M3 - Article

VL - 312

SP - R927-R937

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6

ER -