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 diabetes-induced impairment of long-term hippocampal and prefrontal cortex-mediated fear learning. In conclusion, these findings support the involvement of TLR2 in the pathogenesis of diabetic vascular disease and cognitive impairment.

Identification of Molecular Signatures and Candidate Drugs in Vascular Dementia by Bioinformatics Analyses

“…The protein encoded by TLR2 is a member of the tolllike receptor (TLR) family, whose members are significant pattern recognition receptors of the innate immune system, initiating inflammatory cascades by recognizing pathogen-and damaged-associated molecular patterns. TLR2 was found to play a pivotal role in inflammation after ischemic brain injury (Wang et al, 2011) and was involved in the development of diabetic microvascular complications, including endothelial dysfunction and cognitive impairment (Hardigan et al, 2017). In this study, we found that TLR2 was upregulated in the VaD samples compared with the controls samples, which supports the previous results.…”

Post-stroke neovascularization and functional outcomes differ in diabetes depending on severity of injury and sex: Potential link to hemorrhagic transformation

“…In order to assess cognitive deficits, we used the NOR test (Hardigan et al, 2017; Prakash et al, 2013b). Animals were habituated to test apparatus in a grey plastic box (63L × 38W × 42H cm) that was layered with animal bedding for 4 days prior to baseline testing for 10 min.…”

Impact of Metabolic Diseases on Cerebral Circulation: Structural and Functional Consequences

“…Experimental models have also shown diabetes-mediated temporal and spatial alterations in CBF. In STZ-induced T1D model, CBF is lower early in the disease process whereas the same model later shows increased perfusion (111) (Fig. 8).…”