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

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

Research output: Contribution to journalArticle

9 Scopus citations

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 2017

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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