Tulane Center for Aging and Deming Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA.
Deming Department of Medicine, Tulane University Health Sciences Center, 1430 Tulane Ave., MBC 8513, New Orleans, LA, 70112, USA.
Sci Rep. 2023 Apr 28;13(1):6998. doi: 10.1038/s41598-023-33677-z.
Various risk factors of Alzheimer's disease (AD) are known, such as advanced age, possession of certain genetic variants, accumulation of toxic amyloid-β (Aβ) peptides, and unhealthy lifestyle. An estimate of heritability of AD ranges from 0.13 to 0.25, indicating that its phenotypic variation is accounted for mostly by non-genetic factors. DNA methylation is regarded as an epigenetic mechanism that interfaces the genome with non-genetic factors. The Tg2576 mouse model has been insightful in AD research. These transgenic mice express a mutant form of human amyloid precursor protein linked to familial AD. At 9-13 months of age, these mice show elevated levels of Aβ peptides and cognitive impairment. The current literature lacks integrative multiomics of the animal model. We applied transcriptomics and DNA methylomics to the same brain samples from ~ 11-month-old transgenic mice. We found that genes involved in extracellular matrix structures and functions are transcriptionally upregulated, and genes involved in extracellular protein secretion and localization are differentially methylated in the transgenic mice. Integrative analysis found enrichment of GO terms related to memory and synaptic functionability. Our results indicate a possibility of transcriptional modulation by DNA methylation underlying AD neuropathology.
已知阿尔茨海默病（AD）的各种风险因素，如年龄较大、携带某些遗传变异、有毒淀粉样蛋白-β（Aβ）肽的积累以及不健康的生活方式。AD 的遗传率估计在 0.13 到 0.25 之间，这表明其表型变异主要由非遗传因素决定。DNA 甲基化被认为是一种将基因组与非遗传因素联系起来的表观遗传机制。Tg2576 小鼠模型在 AD 研究中具有启发性。这些转基因小鼠表达与家族性 AD 相关的人类淀粉样前体蛋白的突变形式。在 9-13 个月大时，这些小鼠表现出 Aβ肽水平升高和认知障碍。目前的文献缺乏对动物模型的综合多组学研究。我们将转录组学和 DNA 甲基组学应用于相同的转基因小鼠脑样本。我们发现，参与细胞外基质结构和功能的基因转录上调，参与细胞外蛋白分泌和定位的基因在转基因小鼠中差异甲基化。综合分析发现与记忆和突触功能相关的 GO 术语富集。我们的研究结果表明，AD 神经病理学可能存在由 DNA 甲基化介导的转录调控。
