Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
Institute for Reproduction and Developmental Sciences, Kansas City, KS, USA.
J Alzheimers Dis. 2023;94(2):519-535. doi: 10.3233/JAD-230316.
Alzheimer's disease (AD) brains accumulate DNA double-strand breaks (DSBs), which could contribute to neurodegeneration and dysfunction. The genomic distribution of AD brain DSBs is unclear.
To map genome-wide DSB distributions in AD and age-matched control brains.
We obtained autopsy brain tissue from 3 AD and 3 age-matched control individuals. The donors were men between the ages of 78 to 91. Nuclei extracted from frontal cortex tissue were subjected to Cleavage Under Targets & Release Using Nuclease (CUT&RUN) assay with an antibody against γH2AX, a marker of DSB formation. γH2AX-enriched chromatins were purified and analyzed via high-throughput genomic sequencing.
The AD brains contained 18 times more DSBs than the control brains and the pattern of AD DSBs differed from the control brain pattern. In conjunction with published genome, epigenome, and transcriptome analyses, our data revealed aberrant DSB formation correlates with AD-associated single-nucleotide polymorphisms, increased chromatin accessibility, and upregulated gene expression.
Our data suggest in AD, an accumulation of DSBs at ectopic genomic loci could contribute to an aberrant upregulation of gene expression.
阿尔茨海默病（AD）大脑会积累 DNA 双链断裂（DSBs），这可能导致神经退行性变和功能障碍。AD 大脑 DSB 的基因组分布尚不清楚。
绘制 AD 和年龄匹配对照大脑中全基因组 DSB 分布图谱。
我们从 3 名 AD 和 3 名年龄匹配的对照个体中获得了尸检脑组织。供体为年龄在 78 至 91 岁之间的男性。从额皮质组织中提取的核，用针对 DSB 形成标志物 γH2AX 的抗体进行靶向切割和释放利用核酸酶（CUT&RUN）检测。γH2AX 富集的染色质通过高通量基因组测序进行纯化和分析。
AD 大脑中的 DSB 比对照大脑多 18 倍，AD DSB 的模式与对照大脑模式不同。结合已发表的基因组、表观基因组和转录组分析，我们的数据表明，异常的 DSB 形成与 AD 相关的单核苷酸多态性、染色质可及性增加和上调的基因表达相关。
我们的数据表明，在 AD 中，异位基因组位置的 DSB 积累可能导致基因表达的异常上调。
