Scholarlink

<p>Alzheimer’s disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-β (Aβ) pathology, although the underlying molecular mechanisms remain incompletely understood. Emerging evidence implicates altered DNA methylation (DNAm) in AD but comprehensive analyses in experimental models are limited. Here, we profile DNAm dynamics in two widely used transgenic mouse models of tau (rTg4510) and Aβ (J20) neuropathology, focusing on the entorhinal cortex and hippocampus. Using reduced representation bisulfite sequencing (RRBS) and methylation arrays across multiple disease stages, we identified widespread pathology-associated DNAm alterations in both models. Tau pathology in rTg4510 mice was associated with extensive DNAm remodeling at genes involved in neuronal plasticity, apoptosis, and lipid metabolism, including <i>Dcaf5</i>, <i>Creb3l4</i>, and <i>As3mt</i>. In contrast, J20 mice exhibited more modest changes, primarily at immune-related loci such as <i>Grk2</i>, <i>Ncam2</i>, and <i>Prmt8</i>. Tau-associated DNAm changes were more consistent across brain areas than those associated with Aβ pathology. Comparison with human AD DNAm datasets revealed overlapping DNAm differences, including hypermethylation at <i>Ank1</i> and <i>Prdm16</i> in rTg4510 mice. These findings provide robust evidence for early, pathology-associated epigenetic alterations in AD and highlight the utility of epigenomic profiling in transgenic models for identifying novel targets for early intervention in AD.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer’s disease neuropathology

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月7日

查看全文
  • Szi Kay Leung,
  • Emma M. Walker,
  • Stefania Policicchio,
  • Aisha Dahir,
  • Dorothea Seiler Vellame,
  • Adam R. Smith,
  • Rhian Swarbrick,
  • Katie Lunnon,
  • Emma L. Dempster,
  • Zeshan Ahmed,
  • Eilis Hannon,
  • Isabel Castanho,
  • Jonathan Mill

摘要

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration driven by tau and amyloid-β (Aβ) pathology, although the underlying molecular mechanisms remain incompletely understood. Emerging evidence implicates altered DNA methylation (DNAm) in AD but comprehensive analyses in experimental models are limited. Here, we profile DNAm dynamics in two widely used transgenic mouse models of tau (rTg4510) and Aβ (J20) neuropathology, focusing on the entorhinal cortex and hippocampus. Using reduced representation bisulfite sequencing (RRBS) and methylation arrays across multiple disease stages, we identified widespread pathology-associated DNAm alterations in both models. Tau pathology in rTg4510 mice was associated with extensive DNAm remodeling at genes involved in neuronal plasticity, apoptosis, and lipid metabolism, including Dcaf5, Creb3l4, and As3mt. In contrast, J20 mice exhibited more modest changes, primarily at immune-related loci such as Grk2, Ncam2, and Prmt8. Tau-associated DNAm changes were more consistent across brain areas than those associated with Aβ pathology. Comparison with human AD DNAm datasets revealed overlapping DNAm differences, including hypermethylation at Ank1 and Prdm16 in rTg4510 mice. These findings provide robust evidence for early, pathology-associated epigenetic alterations in AD and highlight the utility of epigenomic profiling in transgenic models for identifying novel targets for early intervention in AD.