肌缩性侧面硬化和前性痴呆的突变减少了内皮TDP-43并导致血脑屏障缺陷
Ashok Cheemala1, Amy L Kimble1, Emily N Burrage1
1Center for Vascular Biology, University of Connecticut School of Medicine, Farmington, CT, USA.
Science advances
|April 16, 2025
概括
脑内皮细胞中核TDP-43 (交易性反应DNA结合蛋白) 的减少会破坏血脑屏障. 这种细胞功能障碍有助于前性痴呆症 (FTD) 和肌缩性侧面硬化症 (ALS) 的特征.
科学领域:
- 神经科学是一个神经科学.
- 细胞生物学 细胞生物学
- 遗传学 是一个遗传学.
背景情况:
- 编码TDP-43的TARDBP基因的突变与FTD和ALS等神经退行性疾病有关.
- 在患有ALS-FTD的个体的内皮细胞 (ECs) 中观察到核TDP-43的减少.
- 增加血脑屏障 (BBB) 透性是ALS-FTD的一个特征.
研究的目的:
- 研究大脑毛细血管内皮细胞 (ECs) 中的减少核TDP-43在FTD和ALS病变发生过程中的作用.
- 为了确定EC中TDP-43缺乏是否会导致BBB功能障碍和神经退行性特征.
主要方法:
- 对具有TDP-43突变的小鼠大脑EC中核TDP-43水平的分析.
- 在大脑EC中条件删除TDP-43,以评估其细胞自主效应.
- 评估BBB完整性,结合综合体和神经病理标志物 (纤维素沉积,化,-Tau).
- 评估受影响小鼠的认知和社会行为.
主要成果:
- 在具有TDP-43突变的小鼠的大脑EC中证实了减少的核TDP-43.
- 在TDP-43降低EC时,发生了结合复合体和BBB完整性的细胞自主损失.
- 在大脑EC中向的TDP-43删除导致了BBB缺陷,纤维素沉积,化,酸积累和行为障碍.
- 缺少TDP-43的ECs的转录形状与患病的大脑ECs的转录形状相似.
结论:
- 大脑EC中TDP-43的核损失是破坏BBB完整性的关键因素.
- 在EC中TDP-43缺陷有助于FTD中观察到的关键病理特征和功能缺陷.
- 在大脑血管系统中准TDP-43可能为FTD和ALS提供治疗策略.
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