氧化三甲胺
神经炎症
小胶质细胞
海马结构
齿状回
化学
海马体
星形胶质细胞
炎症
三甲胺
内分泌学
药理学
医学
免疫学
生物化学
中枢神经系统
摘要
Abstract Background While the ultimate cause(s) for Alzheimer’s disease (AD) are unknown, factors that can modify the risk of its development are clearer. Consumption of a seafood‐rich diet has repeatedly been shown to protect against AD. What is less clear however, is why. Much attention has focussed on omega‐3 fatty acids given their anti‐inflammatory effects in vitro, but translation to human studies have been disappointing. Omega‐3 fatty acids are not the only bioactive components in seafood however. In particular, we have recently shown the dietary methylamine trimethylamine N‐oxide (TMAO), produced by gut microbial metabolism of seafood‐enriched choline, to enhance blood‐brain barrier integrity, prevents glial activation and protect cognitive function following peripheral inflammatory challenge. Methods We investigated whether protective effects of TMAO treatment could be extended to neuroinflammatory challenge. Male C57Bl/6 (n = 6) were pre‐treated for 4 weeks with or without TMAO through the drinking water (0.5g/l) prior to unilateral i.c.v. injection of 4 mg/kg streptozotocin (STZ) or saline vehicle. Two weeks post‐lesioning (continuing TMAO treatment as appropriate) animals were killed and assessment was made of hippocampal inflammation. In parallel, the molecular mechanism of action of TMAO was investigated in vitro using immortalised and primary murine microglia, challenged with oligomeric β‐amyloid (100nM). Results Animals treated with STZ showed significant increases in both microglial and astrocytic density in both the CA1 and dentate gyrus regions of the hippocampus, two weeks post‐lesioning, effects that were almost completely attenuated by TMAO pre‐treatment. Study of oxidative and inflammatory markers is ongoing. In vitro analyses of immortalised and primary microglia showed TMAO pre‐treatment (20 µM, 24 h) to prevent lipopolysaccharide (10 ng/ml) or oligomeric β‐amyloid (100nM)‐induced secretion of TNFα, nitric oxide and reactive oxygen species. Conclusion Together, these data further highlight the importance of TMAO in the gut‐brain axis, and emphasise gut microbial metabolism as a conduit for dietary effects upon the brain. Given that TMAO is ultimately derived from dietary choline, these changes may help explain the well‐known beneficial effects of consumption of a seafood‐rich diet upon dementia risk.
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