TLR4 mutation protects neurovascular function and cognitive decline in high-fat diet-fed mice

Area of Science:

• Neuroscience
• Immunology
• Metabolic Disorders

Background:

• Metabolic syndrome (MS) is a proinflammatory state linked to cardiovascular disease and neuroinflammation.
• Toll-like receptor 4 (TLR4) activation by metabolic factors may drive MS-related chronic inflammation and neurodegeneration.
• This study investigates TLR4's role in brain microcirculation and cognitive function in a high-fat diet (HFD)-induced MS mouse model.

Purpose of the Study:

• To elucidate the role of Toll-like receptor 4 (TLR4) in the cerebral microcirculation and cognitive performance of mice with diet-induced metabolic syndrome (MS).

Main Methods:

• Mice were fed a normal diet (ND) or HFD for 24 weeks; wild-type and TLR4 mutant mice were used.
• Intravital video-microscopy assessed brain microcirculation (capillary density, endothelial function, leukocyte interactions).
• Plasma markers, brain proteins (postsynaptic density protein-95, synaptophysin), and neuroinflammation markers (astrocytic coverage, microglial activation) were analyzed.

Main Results:

• HFD-induced MS caused microcirculatory dysfunction (capillary rarefaction, leukocyte adhesion, endothelial dysfunction) and cognitive decline.
• These MS-related alterations were absent in TLR4-deficient mice.
• Reduced TLR4 activation in wild-type mice on HFD correlated with less cerebral microcirculation inflammation.

Conclusions:

• Toll-like receptor 4 (TLR4) is implicated in the microvascular dysfunction and neuroinflammation characteristic of HFD-induced MS.
• TLR4 may play a causal role in the cognitive deficits observed in metabolic syndrome.