Zhao Jinying, Gu Tongjun, Gao Cheng, Miao Guanhong, Palma-Gudiel Helena, Yu Lei, Yang Jingyun, Wang Yanling, Li Yujing, Lim Junghwa, Li Ronghua, Yao Bing, Wu Hao, Schneider Julie A, Seyfried Nicholas, Grodstein Francine, De Jager Philip L, Jin Peng, Bennett David A
Health Informatics Institute, University of South Florida, Tampa, FL, USA.
Department of Epidemiology, College of Public Health and Health Professions, University of Florida, Gainesville, FL, USA.
Nat Commun. 2025 Mar 22;16(1):2842. doi: 10.1038/s41467-025-58159-w.
5-hydroxymethylcytosine, also known as the sixth DNA base of the genome, plays an important role in brain aging and neurological disorders such as Alzheimer's disease. However, little is known about its genome-wide distribution and its association with Alzheimer's disease pathology. Here, we report a genome-wide profiling of 5-hydroxymethylcytosine in 1079 autopsied brains (dorsolateral prefrontal cortex) of older individuals and assess its association with multiple measures of Alzheimer's disease pathologies, including pathological diagnosis of Alzheimer's disease, amyloid-β load, and PHFtau tangle density. Of 197,765 5-hydroxymethylcytosine regions detected, we identified 2821 differentially hydroxymethylated regions associated with Alzheimer's disease neuropathology after controlling for multiple testing and covariates. Many differentially hydroxymethylated regions are located within known Alzheimer's disease loci, such as RIN3, PLCG2, ITGA2B, and USP6NL. Integrative multi-omics analyses support a potential mechanistic role of 5-hydroxymethylcytosine alterations in Alzheimer's disease. Our study presents a large-scale genome-wide atlas of 5-hydroxymethylcytosine in Alzheimer's brain and offers insight into the mechanism underlying Alzheimer's disease pathogenesis.
5-羟甲基胞嘧啶，也被称为基因组的第六种DNA碱基，在大脑衰老和神经退行性疾病如阿尔茨海默病中发挥着重要作用。然而，人们对其全基因组分布及其与阿尔茨海默病病理学的关联知之甚少。在此，我们报告了对1079名老年人尸检大脑（背外侧前额叶皮质）中5-羟甲基胞嘧啶的全基因组分析，并评估了其与阿尔茨海默病病理学多项指标的关联，包括阿尔茨海默病的病理诊断、淀粉样β蛋白负荷和PHFtau缠结密度。在检测到的197,765个5-羟甲基胞嘧啶区域中，在控制多重检验和协变量后，我们鉴定出2821个与阿尔茨海默病神经病理学相关的差异羟甲基化区域。许多差异羟甲基化区域位于已知的阿尔茨海默病基因座内，如RIN3、PLCG2、ITGA2B和USP6NL。综合多组学分析支持5-羟甲基胞嘧啶改变在阿尔茨海默病中的潜在机制作用。我们的研究展示了阿尔茨海默病大脑中5-羟甲基胞嘧啶的大规模全基因组图谱，并为阿尔茨海默病发病机制的潜在机制提供了见解。
