Toll-like receptor 4 deficiency ameliorates β2-microglobulin induced age-related cognition decline due to neuroinflammation in mice

Abstract

Toll-like receptor 4 (TLR4) is a crucial receptor in neuroinflammation and apoptotic neuronal death, and increasing evidences indicated that β2-microglobulin (B2M) is thought to be a major contributor to age-related cognitive decline. In present study, we designed to investigate the effects of TLR4 on B2M-induced age-related cognitive decline. Wild-type (WT) C57BL/6, TLR4 knockout (TLR4-KO) mice and hippocampal neurons from the two type mice were respectively divided into two groups: (1) Veh group; (2) B2M-treated group. The behavioral responses of mice were measured using Morris Water Maze. Hippocampal neurogenesis and neuronal damage, inflammatory response, apoptosis, synaptic proteins and neurotrophic factors, and TLR4/MyD88/NF-κB signaling pathway proteins were examined using molecular biological or histopathological methods. The results showed that WT mice received B2M in the DG exhibited age-related cognitive declines, increased TLR4 mRNA expression and high levels of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) and apoptotic neuronal death in the hippocampus, which were partially attenuated in TLR4-KO mice. Moreover, in absence of TLR4, B2M treatment improved hippocampus neurogenesis and increased synaptic related proteins. Our cell experiments further demonstrated that deletion of TLR4 could significantly increase synaptic related protein, decrease neuroinflammatory fators, inhibited apoptotic neuronal death, and regulated MyD88/NF-κB signal pathway after B2M treatment. In summary, our results support the TLR4 contributes to B2M-induced age-related cognitive decline due to neuroinflammation and apoptosis through TLR4/MyD88/NF-κB signaling pathway via a modulation of hippocampal neurogenesis and synaptic function. This may provide an important neuroprotective mechanism for improving age-related cognitive decline.

TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

“…In the MWM detection, we found that the latency time of KO mice was significantly reduced compared with WT mice at the second navigation test day. It indicated that KO mice had stronger adaptive ability and memory ability, which was consistent with a previous study that TLR4 deficiency ameliorated cognition decline due to neuroinflammation in mice ( Zhong et al, 2020 ). Following SAH model induced on day 6, the escape latency of WT mice was longer than that of the TLR4 deficiency mice on day 7.…”

The Beneficial Roles of SIRT1 in Neuroinflammation-Related Diseases

“…TLR4 knockout inhibits the expression of inflammatory factors IL-1 β and TNF- α and improves the survival rate after induction of intracerebral hemorrhage (ICH) compared with wild-type (WT) mice [ 108 ]. TLR4 deficiency suppresses the inflammatory factors IL-1 β and TNF- α and improves cognitive dysfunction in β 2-microglobulin- (B2M-) induced age-related cognitive decline compared with WT mice [ 109 ]. Moreover, several studies have demonstrated that SIRT1 regulates neuroinflammation via inhibition of the TLR pathway.…”

BoDV‐1 infection induces neuroinflammation by activating the TLR4/MyD88/IRF5 signaling pathway, leading to learning and memory impairment in rats

“…39 TLR4 is one of the most representative TLRs and has been extensively studied. In the brain, TLR4 is involved in learning and memory, 40 aging, 41 mood, 42 and neurodegenerative diseases such as Parkinson's disease 43 and Alzheimer's disease. 23,44 MyD88 is a common linker protein for all TLRs except TLR3.…”