Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer's Disease.
Human Gray and White Matter Metabolomics to Differentiate APOE and Stage Dependent Changes in Alzheimer's Disease.
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DOI：
10.33696/immunology.3.123
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Lin AL
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文献类型：
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作者：
Hammond TC;Xing X;Yanckello LM;Stromberg A;Chang YH;Nelson PT;Lin AL
阿尔茨海默病（AD）是最常见的痴呆形式，其特征在于β-淀粉样蛋白（Aβ）斑块、tau缠结和神经变性。研究表明，神经变性成分，特别是脑代谢缺陷，比Aβ和tau更能预测AD的严重程度。然而，AD脑组织与正常脑组织的生化组成的详细知识仍然不清楚。在这项研究中，我们对肯塔基州大学AD研究中心脑库中158名社区老年人的脑组织进行了代谢组学分析，以根据白色/灰质类型、载脂蛋白E基因型（ε3与ε4变体）和疾病阶段（早期与晚期）来表征患有和不患有AD的脑的生化特征，因为所有这些因素都会影响代谢过程。我们还使用机器学习来对灰色和白色物质中分离对照和AD的顶级代谢物进行排名。与对照组相比，我们发现谷氨酸和肌酸代谢在灰质中对预测AD更关键，而甘氨酸、脂肪酸、嘧啶、三羧酸（TCA）循环和磷脂酰胆碱代谢在白色物质中更关键。在ε4携带者中，与早期阶段相比，与TCA循环和氧化磷酸化相关的代谢物在晚期阶段突出。在ε3携带者中，与氧化性DNA损伤、抑制性神经递质变化和神经元膜破坏相关的代谢物在晚期比早期突出。在早期疾病中，ε4携带者与ε3携带者相比具有与肾功能差相关的代谢物和改变的神经元固醇代谢，但在晚期疾病中基因型之间几乎没有差异。我们的研究结果表明，代谢在区分AD的APOE和阶段依赖性变化中起着关键作用，并可能有助于精确的生活方式和饮食干预，以减轻早期阶段的AD风险，特别是ε4携带者。
Alzheimer’s disease (AD) is the most common form of dementia with hallmarks of β-amyloid (Aβ) plaques, tau tangles, and neurodegeneration. Studies have shown that neurodegeneration components, especially brain metabolic deficits, are more predictable for AD severity than Aβ and tau. However, detailed knowledge of the biochemical composition of AD brain tissue vs. normal brain tissue remains unclear. In this study, we performed a metabolomics analysis on the brain tissue of 158 community-based older adults in the University of Kentucky AD Research Center brain bank to characterize the biochemical profiles of brains with and without AD based on white/gray matter type, apolipoprotein E genotype (ε3 vs ε4 variants), and disease stage (early vs late) as all these factors influence metabolic processes. We also used machine learning to rank the top metabolites separating controls and AD in gray and white matter. Compared with control samples, we found that glutamate and creatine metabolism were more critical for predicting AD in the gray matter, while glycine, fatty acid, pyrimidine, tricarboxylic acid (TCA) cycle, and phosphatidylcholine metabolism were more critical in the white matter. In ε4 carriers, metabolites associated with the TCA cycle and oxidative phosphorylation were prominent in advanced stages compared to the early stages. In ε3 carriers, metabolites related to oxidative DNA damage, changes in inhibitory neurotransmitters, and disruptions of neuronal membranes were prominent in advanced stages compared to the early stages. In early disease, ε4 carriers had metabolites related to poor kidney function and altered neuronal sterol metabolism compared to ε3 carriers, but there were few differences between genotypes in late disease. Our results indicate that metabolism plays a pivotal role in differentiating APOE- and stage-dependent changes in AD and may facilitate precision lifestyle and dietary interventions to mitigate AD risk in the early stages, especially for ε4 carriers.