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.
Highlights
Literatures have noted that advanced age is the highest risk factor for physiological decline in both physically and psychologically, including decreased neurogenesis and cognitive impairment [1,2,3]
The evidence demonstrated the role of Toll-like receptor 4 (TLR4) in learning and memory function of Alzheimer’s disease (AD), we wondered if TLR4 affected B2M-induced cognition impairment
We tested the effect of B2M, administrated in hippocampus, on cognitive behaviors in WT mice and TLR4-KO mice by Morris water maze test
Summary
Literatures have noted that advanced age is the highest risk factor for physiological decline in both physically and psychologically, including decreased neurogenesis and cognitive impairment [1,2,3]. These mild physiological decline have been shown to increase risk to develop dementia later in life [4]. It has been proposed that alleviating the effect of pro-aging factors may provide an effective approach to rejuvenate aging phenotypes [5, 6]. A subset of blood-borne immune-related factors identified as potential pro-aging factors played an important role in age-related cognitive dysfunction.
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