Involvement of life stress in Late-Onset Alzheimer’s Disease (LOAD) has been evinced in longitudinal cohort epidemiological studies, and endocrinologic evidence suggests involvements of catecholamine and corticosteroid systems in LOAD. Early Life Stress (ELS) rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing. Discussed are relevant ELS studies, and findings from three mitogen-activated protein kinase pathways (JNK/SAPK pathway, ERK pathway, p38/MAPK pathway) relevant for mediating environmental stresses. Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, 224 candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. These loci were combined with 89 gene loci confirmed as LOAD risk genes in previous GWAS and WES. Of the 313 risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. 64 microRNA gene regulation mechanisms were published for the compiled loci. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD. For HPA involvement, a CRHR1 haplotype with MAPT was described, but further association of only HSD11B1 with LOAD found; however, association of FKBP1 and NC3R1 polymorphisms was documented in support of stress influence to LOAD. In the brain insulin system, IGF2R, INSR, INSRR, and plasticity regulator ARC, were associated with LOAD. Pertaining to compromised myelin stability in LOAD, relevant associations were found for BIN1, RELN, SORL1, SORCS1, CNP, MAG, and MOG. Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. The majority of up-to-date epigenomic findings include reported modifications in the well-known LOAD core pathology loci MAPT, BACE1, APP (with FOS, EGR1), PSEN1, PSEN2, and highlight a central role of BDNF. Pertaining to ELS, relevant loci are FKBP5, EGR1, GSK3B; critical roles of inflammation are indicated by CRP, TNFA, NFKB1 modifications; for cholesterol biosynthesis, DHCR24; for myelin stability BIN1, SORL1, CNP; pertaining to (epi)genetic mechanisms, hTERT, MBD2, DNMT1, MTHFR2. Findings on gene regulation were accumulated for BACE1, MAPK signalling, TLR4, BDNF, insulin signalling, with most reports for miR-132 and miR-27. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy.

中文翻译：

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晚发性阿尔茨海默氏痴呆的早期生活压力和表观遗传学：系统评价


纵向队列流行病学研究已证明生活压力与晚发性阿尔茨海默病 (LOAD) 有关，内分泌学证据表明儿茶酚胺和皮质类固醇系统与 LOAD 有关。早期生命应激 (ELS) 啮齿动物模型已成功证明了母体分离的后遗症导致了 LOAD 类似的病理学，从而支持了与 GSK-3beta 相关的胰岛素受体信号传导的作用，促进了 tau 过度磷酸化和淀粉样蛋白形成过程。讨论了相关的 ELS 研究以及与介导环境应激相关的三种丝裂原激活蛋白激酶途径（JNK/SAPK 途径、ERK 途径、p38/MAPK 途径）的发现。进一步考虑了自噬损伤、神经炎症和脑胰岛素抵抗的作用。为了进行荟萃分析评估，从 LOAD 病理生理机制的动物研究综述中提取了 224 个候选基因位点，其中 60 个在人类 LOAD 关联研究中没有阳性结果。这些位点与之前的 GWAS 和 WES 中确认为 LOAD 风险基因的 89 个基因位点组合在一起。在评估的 313 个风险基因位点中，有 35 个人类报告涉及甲基化或组蛋白乙酰化方面的表观基因组修饰。已针对编译的位点发表了 64 个 microRNA 基因调控机制。基因组关联研究支持去甲肾上腺素能系统和糖皮质激素系统与 LOAD 的密切关系。对于 HPA 的参与，描述了具有 MAPT 的 CRHR1 单倍型，但发现仅 HSD11B1 与 LOAD 的进一步关联；然而，FKBP1 和 NC3R1 多态性的关联已被记录支持应激对 LOAD 的影响。 在大脑胰岛素系统中，IGF2R、INSR、INSRR 和可塑性调节剂 ARC 与 LOAD 相关。关于 LOAD 中髓磷脂稳定性受损，发现了 BIN1、RELN、SORL1、SORCS1、CNP、MAG 和 MOG 的相关关联。关于表观遗传修饰，报告了 LOAD 的甲基化变异性和去乙酰化。大多数最新的表观基因组研究结果包括已知的 LOAD 核心病理学位点 MAPT、BACE1、APP（含 FOS、EGR1）、PSEN1、PSEN2 的修饰，并强调了 BDNF 的核心作用。对于ELS，相关位点有FKBP5、EGR1、GSK3B； CRP、TNFA、NFKB1 修饰表明炎症的关键作用；用于胆固醇生物合成，DHCR24；用于髓磷脂稳定性 BIN1、SORL1、CNP；与（表观）遗传机制、hTERT、MBD2、DNMT1、MTHFR2 相关。关于 BACE1、MAPK 信号传导、TLR4、BDNF、胰岛素信号传导的基因调控研究结果不断积累，其中大多数报告涉及 miR-132 和 miR-27。表观基因组研究尚不清楚去甲肾上腺素能信号传导的作用，之前通过 LOAD tau 蛋白病导致的儿童蓝核变性的神经病理学发现证明了这一点。