摘要

       年龄依赖性代谢综合征 (MetS) 是心血管疾病的公认危险因素，但它也导致正常衰老或阿尔茨海默病 (AD) 认知受损的主要风险。然而，关于介导 MetS-大脑相互作用的特定途径知之甚少。在这里，我们进行了第一项研究，将 MetS 变量与大脑全基因组表达和线粒体功能的衰老变化定量联系起来。在六只年轻的成年恒河猴和六只衰老的雌性恒河猴中，我们分析了对记忆/认知功能至关重要的两个主要海马细分区 [适当的海马体，或角状回 (CA) 和齿状回 (DG)] 中的基因表达。在每个区域都鉴定了随着衰老而改变的基因 [衰老相关基因 (ARG)]。反映胰岛素抵抗和血脂异常的血清变量用于构建定量 MetS 指数 (MSI)。这种MSI随着年龄的增长而增加，并与海马线粒体功能（状态III氧化）呈负相关。在 CA 和/或 DG 中鉴定出超过 2000 个 ARG，数量大致相等，但在 CA 中比在 DG 中更多的 ARG 与 MSI 选择性相关。由 MSI 相关 ARG 代表的通路是从基因本体数据库和文献中确定的。特别是，代表糖皮质激素受体 (GR)、染色质组装/组蛋白乙酰转移酶和炎症/免疫通路的上调 CA ARG 与 MSI 密切相关。这些结果表明了一种新模型，其中 MetS 与海马 GR 依赖性转录和表观遗传共激活因子的上调相关，导致线粒体功能降低和大脑能量失调。反过来，这些与 MSI 相关的神经能量变化可能会促进炎症、神经元脆弱性和认知障碍/AD 的风险。 

       Age-dependent metabolic syndrome (MetS) is a recognized risk factor for cardiovascular disease, but it also leads to a major risk of normal aging or cognitive impairment in Alzheimer's disease (AD). However, little is known about the specific pathways that mediate MetS-brain interactions. Here, we conducted the first study that quantitatively linked MetS variables to changes in brain genome-wide expression and mitochondrial function with aging. In six young adult rhesus monkeys and six aging female rhesus monkeys, we analyzed two main hippocampal subdivisions that are critical to memory/cognitive function [appropriate hippocampus, or horny gyrus (CA) and dentate gyrus (DG)] gene expression. In each region, genes that change with aging [Aging-related genes (ARG)] are identified. Serum variables that reflect insulin resistance and dyslipidemia are used to construct a quantitative MetS index (MSI). This MSI increases with age and is negatively correlated with hippocampal mitochondrial function (state III oxidation). There are more than 2000 ARGs identified in CA and/or DG, approximately equal in number, but more ARGs in CA than in DG are associated with MSI selectivity. The pathways represented by MSI-related ARGs are determined from gene ontology databases and literature. In particular, CA ARG, which represents the up-regulation of glucocorticoid receptor (GR), chromatin assembly/histone acetyltransferase, and inflammation/immune pathways, is closely related to MSI. These results indicate a new model in which MetS is associated with the up-regulation of hippocampal GR-dependent transcription and epigenetic co-activators, leading to decreased mitochondrial function and brain energy imbalance. In turn, these changes in nerve energy associated with MSI may contribute to inflammation, neuronal fragility, and the risk of cognitive impairment/AD.

https://www.jneurosci.org/content/30/17/6058.short