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APOE4通过诱导TGFβ介导检查点来破坏阿尔茨海默病中的微质反应

Zhuoran Yin^1,2, Neta Rosenzweig¹, Kilian L Kleemann^1,3

¹Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.

Nature immunology

|September 25, 2023

概括

微质APOE4抑制了阿尔茨海默病 (AD) 中有益的神经退行性反应. 通过向APOE4-ITGB8-TGFβ途径恢复这些反应,为AD提供了一个有希望的治疗策略.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
免疫学免疫学免疫学

背景情况:

APOE4等位基因是晚发性阿尔茨海默病 (AD) 的主要遗传风险因素.
尽管APOE在神经退行性微质 (MGnD) 中富含,但微质APOE4在AD病变发生中的作用尚不清楚.

研究的目的:

研究微质APOE4在MGnD对神经退行反应中的作用.
探索针对AD治疗的微质APOE4通路的治疗策略.

主要方法:

使用了小鼠模型 (P301S tau和APP/PS1) 和人类AD大脑样本.
研究了微质APOE4删除对MGnD表型,Aβ斑块清除和天体细胞交叉交谈的影响.
分析了ITGB8转化生长因子-β (TGFβ) 和Inpp5d信号通路.

主要成果:

微质APOE4在小鼠和人类中负面调节MGnD反应.
微质APOE4的删除恢复了MGnD,通过LGALS3增强了天体细胞交叉交谈,并减少了AD病理.
APOE4-ITGB8-TGFβ通路通过上调微质检查点 (如Inpp5d) 来损害MGnD; Inpp5d的删除恢复了MGnD和斑块清除.

结论:

微质APOE4作为对AD病理学的微质反应的负调节剂.
通过阻断ITGB8-TGFβ信号通路来恢复MGnD表型,为阿尔茨海默病提供了潜在的治疗途径.

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