[DOT1L controls neuronal amyloid precursor protein expres-sion via the p38 MAPK-mediated mitochondrial dynamics homeostasis axis]

作者：Zhang Y, Zhu F, Wu X, Li Z, Huang P, Gao Y, Zeng L · 发表于：Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 年份：2026 · DOI：10.3724/zdxbyxb-2025-0706 · 被引用次数：44 · 研究领域：Amyloid beta-Protein Precursor、p38 Mitogen-Activated Protein Kinases、Alzheimer Disease、Mitochondrial Dynamics、Histone-Lysine N-Methyltransferase、Animals、Mice、Mice, Transgenic、Homeostasis、Neurons、Humans、Mitochondria

OBJECTIVES: To investigate the regulatory role of epigenetic regulator disruptor of telomeric silencing 1-like (DOT1L) and its mediated histone H3 lysine 79 (H3K79) methylation in modulating neuronal amyloid precursor protein (APP) expression, and to elucidate the underlying mechanisms involving mitochondrial dynamics homeo-stasis and the upstream p38 mitogen-activated protein kinase (p38 MAPK). METHODS: Alzheimer's disease (AD) models were established using APP/presenilin-1 (APP/PS1) double-transgenic mice and N2a cells overexpressing the human Swedish mutant APP (N2a-APPswe). Immunofluorescence staining was employed to assess DOT1L expression and localization in mouse brain tissues. N2a-APPswe cells were treated with the DOT1L-specific inhibitor EPZ5676 and divided into four groups: blank control, solvent control, DOT1L inhibitor, and DOT1L inhibitor plus p38 agonist (Gynostemma pentaphyllum extract). Western blotting was performed to measure the phosphorylation levels of DRP1 at Ser616 and Ser637, the levels of autophagy-related proteins p62 and the LC3-Ⅱ/LC3-Ⅰ ratio, the phosphorylation level of p38 MAPK, as well as the expression of APP and APP-processing proteins BACE1 and PS1. Reverse transcription quantitative polymerase chain reaction was used to detect mRNA levels of APP and genes involved in mitochondrial fission and fusion. Proteomics data were systematically analyzed through Gene Ontology analysis, WikiPathways enrichment analysis, and STRING protein-protein int...