Trimethylamine N-Oxide Reduces Neurite Density and Plaque Intensity in a Murine Model of Alzheimer's Disease.
Trimethylamine N-Oxide Reduces Neurite Density and Plaque Intensity in a Murine Model of Alzheimer's Disease.
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DOI：
10.3233/jad-220413
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发表时间：
2022
影响因子：
4
通讯作者：
Ulland, Tyler K.
中科院分区：
文献类型：
--
作者：
Zarbock, Katie R.;Han, Jessica H.;Singh, Ajay P.;Thomas, Sydney P.;Bendlin, Barbara B.;Denu, John M.;Yu, John-Paul J.;Rey, Federico E.;Ulland, Tyler K.
阿尔茨海默病（Alzheimer's disease，AD）是最常见的与衰老相关的神经退行性疾病，其病因和进展至今仍不完全清楚。我们以前已经表明，微生物衍生的代谢产物三甲胺N-氧化物（TMAO）在AD所致认知障碍个体的脑脊液（CSF）中升高，并与缠结、斑块和神经元病理学的CSF生物标志物增加呈正相关。我们评估了TMAO对AD进展的直接影响。为此，向转基因5XFAD小鼠补充TMAO 12周。神经突密度通过定量脑显微结构成像与神经突方向分散和密度成像磁共振成像（MRI）进行评估。无标记，定量蛋白质组学进行皮质裂解物从TMAO处理和未处理的动物。通过荧光免疫组织化学评估β淀粉样蛋白斑块、星形胶质细胞和小胶质细胞，并通过蛋白质印迹定量突触蛋白表达。口服TMAO给药导致大脑几个区域的神经突密度显著降低。β淀粉样蛋白斑块平均强度降低，而斑块计数和大小保持不变。蛋白质组学分析显示，TMAO治疗影响了5XFAD小鼠中30种蛋白质（1.5倍截止值）的表达，包括已知影响神经元健康和淀粉样蛋白-β前体蛋白加工的蛋白质。TMAO治疗没有改变星形胶质细胞和小胶质细胞的反应，也没有皮质突触蛋白的表达。这些数据表明，升高的血浆TMAO通过神经突密度的降低影响AD病理学。
Alzheimer’s disease (AD) is the most common aging-associated neurodegenerative disease; nevertheless, the etiology and progression of the disease is still incompletely understood. We have previously shown that the microbially-derived metabolite trimethylamine N-oxide (TMAO) is elevated in the cerebrospinal fluid (CSF) of individuals with cognitive impairment due to AD and positively correlates with increases in CSF biomarkers for tangle, plaque, and neuronal pathology. We assessed the direct impact of TMAO on AD progression. To do so, transgenic 5XFAD mice were supplemented with TMAO for 12 weeks. Neurite density was assessed through quantitative brain microstructure imaging with neurite orientation dispersion and density imaging magnetic resonance imaging (MRI). Label-free, quantitative proteomics was performed on cortex lysates from TMAO-treated and untreated animals. Amyloid-β plaques, astrocytes, and microglia were assessed by fluorescent immunohistochemistry and synaptic protein expression was quantified via western blot. Oral TMAO administration resulted in significantly reduced neurite density in several regions of the brain. Amyloid-β plaque mean intensity was reduced, while plaque count and size remained unaltered. Proteomics analysis revealed that TMAO treatment impacted the expression of 30 proteins (1.5-fold cut-off) in 5XFAD mice, including proteins known to influence neuronal health and amyloid-β precursor protein processing. TMAO treatment did not alter astrocyte and microglial response nor cortical synaptic protein expression. These data suggest that elevated plasma TMAO impacts AD pathology via reductions in neurite density.