Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer's Disease.
Metabolic Network Analysis Reveals Altered Bile Acid Synthesis and Metabolism in Alzheimer's Disease.
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DOI：
10.1016/j.xcrm.2020.100138
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发表时间：
2020-11-17
期刊：
影响因子：
--
通讯作者：
Price ND
中科院分区：
文献类型：
--
作者：
Baloni P;Funk CC;Yan J;Yurkovich JT;Kueider-Paisley A;Nho K;Heinken A;Jia W;Mahmoudiandehkordi S;Louie G;Saykin AJ;Arnold M;Kastenmüller G;Griffiths WJ;Thiele I;Alzheimer’s Disease Metabolomics Consortium;Kaddurah-Daouk R;Price ND
越来越多的证据表明，阿尔茨海默病（AD）的病理生理受到初级和次级胆汁酸的影响，胆汁酸是胆固醇代谢的最终产物。我们分析了2114个死后脑转录组，并确定了在大脑中表达胆汁酸合成途径的基因。从111个人的死后脑样本中测量的初级和次级胆汁酸的靶向代谢组学分析支持这些结果。我们的代谢网络分析表明，牛磺酸运输、胆汁酸合成和胆固醇代谢在AD和认知正常的个体中是不同的。我们还确定了可能调节代谢基因并影响AD代谢改变的转录因子。有趣的是，在脑组织中测量到的一些胆汁酸不能用负责它们合成的酶的存在来解释，这表明它们可能起源于肠道微生物群并被运送到大脑。这些发现激发了对阿尔茨海默病中胆汁酸代谢的进一步研究，以阐明其与认知能力下降的可能联系。与阿尔茨海默病（AD）相关的胆固醇和胆汁酸代谢改变死后大脑中胆汁酸途径基因表达的证据代谢组学分析显示，继发胆汁酸与认知能力下降有关。大脑区域的基因组尺度代谢网络确定了与AD相关的反应。Baloni等人使用系统生物学方法确定了阿尔茨海默病（AD）中胆固醇和胆汁酸代谢的改变。替代胆汁酸和神经胆固醇清除途径以及牛磺酸和胆汁酸转运蛋白的表达提示肠脑轴在AD中的作用。
Increasing evidence suggests Alzheimer's disease (AD) pathophysiology is influenced by primary and secondary bile acids, the end product of cholesterol metabolism. We analyze 2,114 post-mortem brain transcriptomes and identify genes in the alternative bile acid synthesis pathway to be expressed in the brain. A targeted metabolomic analysis of primary and secondary bile acids measured from post-mortem brain samples of 111 individuals supports these results. Our metabolic network analysis suggests that taurine transport, bile acid synthesis, and cholesterol metabolism differ in AD and cognitively normal individuals. We also identify putative transcription factors regulating metabolic genes and influencing altered metabolism in AD. Intriguingly, some bile acids measured in brain tissue cannot be explained by the presence of enzymes responsible for their synthesis, suggesting that they may originate from the gut microbiome and are transported to the brain. These findings motivate further research into bile acid metabolism in AD to elucidate their possible connection to cognitive decline. Altered cholesterol and bile acid metabolism linked to Alzheimer disease (AD) Evidence for alternative bile acid pathway genes expression in post-mortem brains Metabolomics analysis shows secondary bile acids associated with cognitive decline Genome-scale metabolic networks of brain regions identify reactions linked to AD Baloni et al. use a systems biology approach to identify alterations in cholesterol and bile acid metabolism in Alzheimer disease (AD). Expression of alternative bile acid and neural cholesterol clearance pathway along with transporters of taurine and bile acids suggest the role of the gut-brain axis in AD.
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影响因子：
--
作者：
Chiang JY
通讯作者：
Chiang JY
影响因子：
9.9
作者：
Ament, Seth A.;Pearl, Jocelynn R.;Price, Nathan D.
通讯作者：
Price, Nathan D.
影响因子：
9.8
作者：
De Jager, Philip L.;Ma, Yiyi;Bennett, David A.
通讯作者：
Bennett, David A.
影响因子：
5.8
作者：
Chiang JY
通讯作者：
Chiang JY
影响因子：
7.4
作者：
Griffiths, William J.;Abdel-Khalik, Jonas;Wang, Yuqin
通讯作者：
Wang, Yuqin