在阿尔茨海默氏病的大脑中,TYK2调解了TDP-43病理学的神经炎症
Laura E König1,2, Steve Rodriguez1,2, Clemens Hug1
1Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, 02115, MA, USA.
Nature communications
|March 15, 2026
概括
细胞质dsRNA在阿尔茨海默氏症和ALS中触发神经炎症. 用诸如deucravacitinib这样的药物阻断TYK2酶显示出保护作用,表明TYK2是这些神经退行性疾病的潜在治疗标.
科学领域:
- 神经科学是一个神经科学.
- 免疫学 免疫学 免疫学
- 遗传学 是一个遗传学.
背景情况:
- 神经炎症是神经退行性疾病的关键特征,如阿尔茨海默氏症 (AD) 和骨髓缩侧面硬化症 (ALS).
- 细胞质双链RNA (cdsRNA) 激活神经细胞中的I型干扰素反应,导致细胞死亡,并且在C9ORF72-ALS患者的神经元中观察到.
研究的目的:
- 研究cdsRNA,TDP-43病理和AD和ALS中神经炎症之间的联系.
- 为了确定TDP-43蛋白病变的潜在治疗点.
主要方法:
- 在人死后脑组织中对cdsRNA和pTDP-43的空间巧合分析.
- 分析受影响大脑区域的干扰素反应基因.
- 使用人类TDP-43 G298S诱导多能干细胞 (iPSC) 皮层神经元模型.
- 采用神秘的外子探测作为TDP-43错位化的代理.
- 测试FDA批准的JAK抑制剂 (巴里西提尼布,鲁克索利提尼布) 和选择性TYK2抑制剂 (德乌克拉维西提尼布).
- 执行CRISPR屏幕以识别遗传修饰剂.
主要成果:
- 在AD脑组织中观察到cdsRNA和pTDP-43内置之间的空间重叠,以及调高干扰素反应基因.
- 在人类TDP-43 G298S iPSC神经元模型中证实了cdsRNA的积累.
- 雅克抑制剂在具有高密码外子表达的模型中特别表现出保护作用.
- 在CRISPR查中,TYK2被确定为关键因素,TYK2被淘汰,deucravacitinib拯救了cdsRNA诱导的毒性.
结论:
- 与TDP-43相关的神经退行性疾病,包括AD和C9ORF72-ALS,共享依赖于TYK2.2.的并行神经炎症机制.
- 对于这些疾病,TYK2是潜在的疾病修饰性治疗点.
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