Ramirez Aura M, Nasciben Luciana Bertholim, Moura Sofia, Coombs Lauren, Rajabli Farid, DeRosa Brooke A, Whitehead Patrice L, Adams Larry D, Starks Takiyah D, Mena Pedro R, Illanes-Manrique Maryenela, Tejada Sergio, Byrd Goldie S, Caban-Holt Allison, Cuccaro Michael L, McInerney Katalina, Cornejo-Olivas Mario R, Feliciano-Astacio Briseida E, Wang Liyong, Robayo Maria C, Xu Wanying, Jin Fulai, Pericak-Vance Margaret A, Griswold Anthony J, Young Juan I, Dykxhoorn Derek M, Vance Jeffery M
John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, Florida, USA.
Alzheimers Dement. 2025 Sep;21(9):e70593. doi: 10.1002/alz.70593.
This study investigates ancestry-specific changes in induced pluripotent stem cell (iPSC)-derived oligodendroglia genomic regulation in Alzheimer's disease (AD), addressing diversity gaps by including African, Amerindian, and European ancestries in the analysis.
We generated 12 iPSC lines from AD patients and controls with different apolipoprotein E (APOE) genotypes, APOE ε3/ ε3 and APOE ε4/ ε4, across three ancestries. Lines were differentiated into neural spheroids containing oligodendrocyte lineage cells and analyzed by single-nucleus RNA sequencing, Assay for Transposase-Accessible Chromatin with sequencing (ATACseq)APO, and High-throughput Chromosome Conformation Capture (Hi-C).
We identified ancestry-specific differences in gene expression and chromatin accessibility of AD genome-wide association study candidate genes. APOE ε4/ ε4 carriers across all ancestries showed upregulated cholesterol biosynthesis genes with decreased myelination markers. iPSC-derived oligodendrocytes demonstrated high correlation (R > 0.85) with human brain transcriptomes.
Our findings highlight the importance of studying diverse ancestries in AD research and suggest early APOE ε4 effects on cholesterol metabolism. The validated iPSC model provides a valuable tool for investigating ancestry-specific disease mechanisms.
First study comparing iPSC-derived oligodendroglia across three ancestries. APOE ε4 carriers show upregulated cholesterol synthesis in oligodendroglia. Reduced myelin gene expression observed in APOE ε4/ε4 oligodendroglia. Ancestry-specific differences found in AD GWAS genes and chromatin states. Novel insights into oligodendrocyte biology relevant to Alzheimer's disease.
本研究调查了阿尔茨海默病（AD）中诱导多能干细胞（iPSC）衍生的少突胶质细胞基因组调控的特定祖先变化，通过在分析中纳入非洲、美洲印第安人和欧洲血统来解决多样性差距问题。
我们从患有不同载脂蛋白E（APOE）基因型（APOE ε3/ε3和APOE ε4/ε4）的AD患者和对照中，跨越三个血统生成了12个iPSC系。将这些细胞系分化为含有少突胶质细胞谱系细胞的神经球，并通过单核RNA测序、转座酶可及染色质测序分析（ATACseq）、APO和高通量染色体构象捕获（Hi-C）进行分析。
我们在AD全基因组关联研究候选基因的基因表达和染色质可及性方面发现了特定祖先差异。所有血统的APOE ε4/ε4携带者均显示胆固醇生物合成基因上调，髓鞘形成标记物减少。iPSC衍生的少突胶质细胞与人脑转录组显示出高度相关性（R>0.85）。
我们的研究结果突出了在AD研究中研究不同血统的重要性，并提示APOE ε4对胆固醇代谢的早期影响。经过验证的iPSC模型为研究特定祖先的疾病机制提供了有价值的工具。
首次比较三个血统的iPSC衍生少突胶质细胞的研究。APOE ε4携带者在少突胶质细胞中显示胆固醇合成上调。在APOE ε4/ε4少突胶质细胞中观察到髓鞘基因表达减少。在AD全基因组关联研究基因和染色质状态中发现特定祖先差异。对与阿尔茨海默病相关的少突胶质细胞生物学有了新见解。
